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Effects of subcutaneous esketamine on blood pressure and heart rate in treatment-resistant depression. Del Sant Lorena Catarina,Sarin Luciana Maria,Magalhães Eduardo Jorge Muniz,Lucchese Ana Cecília,Tuena Marco Aurélio,Nakahira Carolina,Fava Victor Augusto Rodovalho,Delfino Rodrigo,Surjan Juliana,Steiglich Matheus Souza,Barbosa Matheus,Abdo Guilherme,Cohrs Frederico Molina,Liberatori Aroldo,Del Porto José Alberto,Lacerda Acioly Luiz Tavares,de Jesus Mari Jair Journal of psychopharmacology (Oxford, England) INTRODUCTION AND OBJECTIVES:The impact of multiple subcutaneous (s.c.) esketamine injections on the blood pressure (BP) and heart rate (HR) of patients with unipolar and bipolar treatment-resistant depression (TRD) is poorly understood. This study aimed to assess the cardiovascular safety of multiple s.c. doses of esketamine in patients with TRD. METHODS:Seventy TRD patients received 394 weekly s.c. esketamine injections in conjunction with oral antidepressant therapy for up to six weeks. Weekly esketamine doses were 0.5, 0.75 or 1.0 mg/kg according to each patient's response to treatment. Participants were monitored before each treatment and every 15 minutes thereafter for 120 minutes. We assessed systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR measurements for the entire treatment course. RESULTS:BP increased after the first s.c. esketamine injection, reaching maximum mean SBP/DBP levels of 4.87/5.54 mmHg within 30-45 minutes. At the end of monitoring, 120 minutes post dose, vital signs returned to pretreatment levels. We did not detect significant differences in BP between doses of 0.5, 0.75, and 1 mg/kg esketamine. Mean HR did not differ significantly between doses or before and after s.c. esketamine injection. CONCLUSIONS:The BP changes observed with repeated s.c. esketamine injections were mild and well tolerated for doses up to 1 mg/kg. The s.c. route is a simple and safe method of esketamine administration, even for patients with clinical comorbidities, including obesity, hypertension, diabetes, and dyslipidemia. However, 14/70 patients experienced treatment-emergent transient hypertension (SBP >180 mmHg and/or a DBP >110 mmHg). Therefore, we strongly recommend monitoring BP for 90 minutes after esketamine dosing. Since s.c. esketamine is cheap, requires less frequent dosing (once a week), and is a simpler procedure compared to intravenous infusions, it might have an impact on public health. 10.1177/0269881120922955
Esketamine for treatment-resistant depression: seven concerns about efficacy and FDA approval. The lancet. Psychiatry 10.1016/S2215-0366(19)30394-3
Rapid inflammation modulation and antidepressant efficacy of a low-dose ketamine infusion in treatment-resistant depression: A randomized, double-blind control study. Chen Mu-Hong,Li Cheng-Ta,Lin Wei-Chen,Hong Chen-Jee,Tu Pei-Chi,Bai Ya-Mei,Cheng Chih-Ming,Su Tung-Ping Psychiatry research Increasing evidence supports the rapid antidepressant effect of a low-dose ketamine infusion in treatment-resistant depression (TRD). Proinflammatory cytokines play a crucial role in the pathophysiology of TRD. However, it is unknown whether the rapid antidepressant effect of ketamine is related to the rapid suppression of proinflammatory cytokines. Seventy-one patients with TRD were randomized into three groups according to the treatment received: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, and normal saline infusion. Proinflammatory markers, including C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α were examined at baseline and at 40 min, 240 min, Day 3, and Day 7 postinfusion. Montgomery-Åsberg Depression Rating Scale (MADRS) was assessed for depressive symptoms across time. Log-transformed IL-6 and TNF-α levels differed significantly over time. The decrease in TNF-α between baseline and 40 min postinfusion was positively correlated with a decrease in MADRS scores across time in the 0.5 mg/kg ketamine group. This is the first clinical study to support a positive correlation between changes in cytokine levels after ketamine infusion and improvements in depressive symptoms with TRD. The rapid suppression of proinflammatory cytokines may contribute to the rapid antidepressant effect of the ketamine infusion. 10.1016/j.psychres.2018.08.078
Cognitive function of patients with treatment-resistant depression after a single low dose of ketamine infusion. Chen Mu-Hong,Li Cheng-Ta,Lin Wei-Chen,Hong Chen-Jee,Tu Pei-Chi,Bai Ya-Mei,Cheng Chih-Ming,Su Tung-Ping Journal of affective disorders BACKGROUND:Clinical and animal studies have reported conflicting results regarding the effect of ketamine on cognitive function, although increasing evidence supports a rapid and sustained antidepressant effect of a subanesthetic dose of ketamine infusion for patients with treatment-resistant depression (TRD). However, the cognitive function before and after ketamine infusion was rarely investigated in patients with TRD. METHODS:A total of 71 adult patients with TRD were enrolled and randomized to 0.5-mg/kg ketamine, 0.2-mg/kg ketamine, or normal saline infusion groups. Depressive symptoms were measured using the Hamilton Depression Rating Scale at baseline and at different time points post ketamine infusion. Cognitive function was evaluated using working memory and go/no-go tasks at baseline, Day 3, and Day 14 post ketamine infusion. RESULTS:A single low dose of ketamine infusion did not impair the cognitive function of patients with TRD. The paired t test revealed that patients with TRD receiving 0.5 mg/kg of ketamine infusion exhibited a slight improvement in sustained attention and response control measured using the go/no-go task at Day 14 post ketamine infusion. A significant association was also observed between depressive symptoms and cognitive function changes at Day 3 in the 0.5-mg/kg ketamine infusion group. DISCUSSION:A 0.5 mg/kg dose of ketamine infusion was not harmful, but slightly beneficial, for the cognitive function of patients with TRD. Additional studies are necessary to elucidate the effects of repeated ketamine infusion on cognitive function. 10.1016/j.jad.2018.07.033
Adjunctive Intranasal Esketamine in Treatment-Resistant Depression-Reply. Daly Ella J,Singh Jaskaran B JAMA psychiatry 10.1001/jamapsychiatry.2018.0430
Rapid-acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective. Hashimoto Kenji Psychiatry and clinical neurosciences Major depressive disorder (MDD) is one of the most disabling psychiatric disorders. Approximately one-third of the patients with MDD are treatment resistant to the current antidepressants. There is also a significant therapeutic time lag of weeks to months. Furthermore, depression in patients with bipolar disorder (BD) is typically poorly responsive to antidepressants. Therefore, there exists an unmet medical need for rapidly acting antidepressants with beneficial effects in treatment-resistant patients with MDD or BD. Accumulating evidence suggests that the N-methyl-D-aspartate receptor (NMDAR) antagonist ketamine produces rapid and sustained antidepressant effects in treatment-resistant patients with MDD or BD. Ketamine is a racemic mixture comprising equal parts of (R)-ketamine (or arketamine) and (S)-ketamine (or esketamine). Because (S)-ketamine has higher affinity for NMDAR than (R)-ketamine, esketamine was developed as an antidepressant. On 5 March 2019, esketamine nasal spray was approved by the US Food and Drug Administration. However, preclinical data suggest that (R)-ketamine exerts greater potency and longer-lasting antidepressant effects than (S)-ketamine in animal models of depression and that (R)-ketamine has less detrimental side-effects than (R,S)-ketamine or (S)-ketamine. In this article, the author reviews the historical overview of the antidepressant actions of enantiomers of ketamine and its major metabolites norketamine and hydroxynorketamine. Furthermore, the author discusses the other potential rapid-acting antidepressant candidates (i.e., NMDAR antagonists and modulators, low-voltage-sensitive T-type calcium channel inhibitor, potassium channel Kir4.1 inhibitor, negative modulators of γ-aminobutyric acid, and type A [GABA ] receptors) to compare them with ketamine. Moreover, the molecular and cellular mechanisms of ketamine's antidepressant effects are discussed. 10.1111/pcn.12902
Efficacy and Safety of Esketamine Nasal Spray Plus an Oral Antidepressant in Elderly Patients With Treatment-Resistant Depression-TRANSFORM-3. Ochs-Ross Rachel,Daly Ella J,Zhang Yun,Lane Rosanne,Lim Pilar,Morrison Randall L,Hough David,Manji Husseini,Drevets Wayne C,Sanacora Gerard,Steffens David C,Adler Caleb,McShane Rupert,Gaillard Raphaël,Wilkinson Samuel T,Singh Jaskaran B The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 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-Åsberg 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 <55 years and 3.1 (-4.51, 10.80; t = 0.8, two-sided nominal p = 0.407) for those ≥55 years. Patients who rolled over into the long-term open-label study showed continued improvement with esketamine following 4 additional treatment weeks. 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 (<55 years). 10.1016/j.jagp.2019.10.008
The Efficacy and Safety of Esketamine for the Treatment-Resistant Depression in Older Adults: Comments on TRANSFORM-3 Trial Results. Lavretsky Helen,Roose Steven P The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 10.1016/j.jagp.2019.10.009
Persistent antidepressant effect of low-dose ketamine and activation in the supplementary motor area and anterior cingulate cortex in treatment-resistant depression: A randomized control study. Chen Mu-Hong,Li Cheng-Ta,Lin Wei-Chen,Hong Chen-Jee,Tu Pei-Chi,Bai Ya-Mei,Cheng Chih-Ming,Su Tung-Ping Journal of affective disorders BACKGROUND:A single low-dose ketamine infusion exhibited a rapid antidepressant effect within 1h. Despite its short biological half-life (approximately 3h), the antidepressant effect of ketamine has been demonstrated to persist for several days. However, changes in brain function responsible for the persistent antidepressant effect of a single low-dose ketamine infusion remain unclear METHODS: Twenty-four patients with treatment-resistant depression (TRD) were randomized into three groups according to the treatment received: 0.5mg/kg ketamine, 0.2mg/kg ketamine, and normal saline infusion. Standardized uptake values (SUVs) of glucose metabolism measured through F-FDG positron-emission-tomography before infusion and 1day after a 40-min ketamine or normal saline infusion were used for subsequent whole-brain voxel-wise analysis and were correlated with depressive symptoms, as defined using the Hamilton Depression Rating Scale-17 (HDRS-17) score RESULTS: The voxel-wise analysis revealed that patients with TRD receiving the 0.5mg/kg ketamine infusion had significantly higher SUVs (corrected for family-wise errors, P = 0.014) in the supplementary motor area (SMA) and dorsal anterior cingulate cortex (dACC) than did those receiving the 0.2mg/kg ketamine infusion. The increase in the SUV in the dACC was negatively correlated with depressive symptoms at 1day after ketamine infusion DISCUSSION: The persistent antidepressant effect of a 0.5mg/kg ketamine infusion may be mediated by increased activation in the SMA and dACC. The higher increase in dACC activation was related to the reduction in depressive symptoms after ketamine infusion. A 0.5mg/kg ketamine infusion facilitated the glutamatergic neurotransmission in the SMA and dACC, which may be responsible for the persistent antidepressant effect of ketamine much beyond its half-life. 10.1016/j.jad.2017.09.008
Impact of oral ketamine augmentation on hospital admissions in treatment-resistant depression and PTSD: a retrospective study. Hartberg John,Garrett-Walcott Simone,De Gioannis Angelo Psychopharmacology RATIONALE:Depressive episodes are the leading cause of mental health-related hospital admissions in Australia, and 44% of those admitted have a previous history of hospitalisations for depression (Admitted patient mental health-related care: (Australian Institute of Health and Welfare Aust Hospital Stat 2011-12, 2013). Despite numerous available antidepressant treatments, many patients do not respond to conventional therapy, having what is called 'treatment resistance' (Fava Biol Psychiatry 53:649-659, 2003). In recent years, ketamine has risen to prominence as an effective, rapidly acting antidepressant (Ketamine: a light in the darkness: Paleos and Ross 28-33, 2013). However, customary intravenous (IV) and intramuscular (IM) routes of administration and relapse rates after cessation remain barriers to more widely adopted usage. OBJECTIVES:This study represents the largest retrospective review of patients receiving long-term oral ketamine for treatment-resistant depression and post-traumatic stress disorder (PTSD). Our purpose was to examine the safety and efficacy of oral ketamine therapy in an outpatient setting as measured by changes in hospitalisation for psychiatric episodes. METHODS:Hospital records of 37 patients who received oral ketamine treatment were reviewed to compare the number and duration of psychiatric hospital admissions before and after treatment. Records were also screened for adverse medical events and changes in ketamine dosage over time. RESULTS:Following treatment, inpatient hospital days were reduced by 70%, and hospital admissions were reduced by 65%. The dose of ketamine patients required was stable over time with no evidence of tolerance building. There were no serious adverse events and no long-term negative effects associated with ketamine. CONCLUSIONS:Oral ketamine offers a promising pharmacologic adjunct to depression treatment. It may offer a more approachable alternative to IV or IM ketamine. The results warrant further investigation into the safety and efficacy of oral ketamine for psychiatric treatment. 10.1007/s00213-017-4786-3
Short-term ketamine administration in treatment-resistant depression: focus on cardiovascular safety. Szarmach Joanna,Cubała Wiesław Jerzy,Włodarczyk Adam,Wiglusz Mariusz S Psychiatria Danubina Ketamine is an anaesthetic and analgesic agent that demonstrates the antidepressive effect in major depression. Several administrations routes, dosing schemas and esketamine are investigated in basic and clinical research with particular focus on treatment-resistant depression (TRD) where drug demonstrates its efficacy where very limited alternatives are available. The majority of ketamine studies in TRD treatment reported no serious adverse events regardless the administration route or regimen. However, the most commonly observed adverse events following ketamine administration in antidepressive doses include general, psychotomimetic, dissociative and hemodynamic ones. The side effects are mild or moderate, well-tolerated and transient. This paper discusses the risks regarding cardiovascular safety in MDD patients in short-term ketamine administration with particular focus on the effect on blood pressure and adverse drug reactions mitigation measures. The increase in systolic (SBP) and diastolic (DBP) blood pressure is dose-dependent and begins shortly after administration peaking at around 30 to 50 minutes with SBP and DBP rise from 10% to 50% above predose values and resolving at approximately 2 to 4 hours after the dose administration. These changes generally are primarily asymptomatic. The elevations in SBP and DBP are observed on each dosing day with multiple administration schema. The treatment with ketamine and esketamine is contradicted in subjects at risk of an increase in blood pressure or intracranial pressure. The current evidence indicates the blood pressure should be assessed prior to dosing with ketamine and hypertensive individuals shall receive effective lifestyle/pharmacologic management prior to treatment. Blood pressure should be monitored after dose administration until blood pressure returns to acceptable levels. If blood pressure remains elevated acute blood pressure management shall be delivered. In patients experiencing symptoms of hypertensive crisis immediate emergency care must be provided. The unmet need for improved pharmacotherapies for TRD means the use of ketamine and esketamine is warranted therapeutic option in patients who fail to achieve a sustained remission of depressive symptoms with drugs with monoamine-based mechanisms of action. Adequate safety measures must be applied when using ketamine/esketamine in TRD subjects with particular focus on somatic comorbidities as the transient drug effect on cardiovascular system is demonstrated and of clinical significance.
Ketamine and Treatment-Resistant Depression. Lent Jennifer K,Arredondo Albert,Pugh Marilyn A,Austin Paul N AANA journal Major depressive disorder affects tens of millions of people each year. One-third of those affected have depression that is resistant to conventional pharmacologic, psychologic, or somatic treatments. Patients with treatment-resistant depression have few remedies other than electroconvulsive therapy or transcranial magnetic stimulation. Recent research has highlighted the promising antidepressant effects of subanesthetic ketamine infusions. This journal course examines the efficacy of ketamine for treatment-resistant depression. Evidence from 10 systematic reviews and randomized controlled trials suggest that most of the researchers concluded ketamine significantly decreased depression severity ratings at short-term assessment intervals, whereas evidence examining the long-term effects is lacking. Ketamine infusion therapy was generally well tolerated, with minimal untoward effects. Large, randomized controlled trials are needed to discern the longer-term efficacy, tolerance, and dependence profiles of ketamine infusions. Optimal dosing schedules to best prolong the antidepressant effects of ketamine have yet to be determined.
Efficacy, Safety, and Durability of Repeated Ketamine Infusions for Comorbid Posttraumatic Stress Disorder and Treatment-Resistant Depression. Albott C Sophia,Lim Kelvin O,Forbes Miriam K,Erbes Christopher,Tye Susanna J,Grabowski John G,Thuras Paul,Batres-Y-Carr Tegan M,Wels Joseph,Shiroma Paulo R The Journal of clinical psychiatry OBJECTIVE:The present study examined the efficacy, safety, and durability of repeated ketamine infusions for the treatment of comorbid posttraumatic stress disorder (PTSD) and treatment-resistant depression (TRD) in a sample of veterans. METHODS:Individuals with comorbid DSM-5-defined PTSD and DSM-IV-defined major depressive disorder (N = 15) received 6 intravenous ketamine infusions (0.5 mg/kg) on a Monday-Wednesday-Friday schedule over a 12-day period from May 2015 to June 2016. Data from outcome measures were collected before and 24 hours after each infusion and weekly for 8 weeks following the final infusion. RESULTS:Continuous measures of symptom change were significant for both disorders and were associated with large effect sizes (mean decrease in PTSD Checklist for DSM-5 score = 33.3 points [95% CI, 23.0-43.5 points], P < .0005, sample size-adjusted Cohen d [d'] = 2.17; mean decrease in Montgomery-Asberg Depression Rating Scale score = 26.6 points [95% CI, 23.0-30.2 points], P < .0005, d' = 4.64). The remission rate for PTSD was 80.0%, and the response rate for TRD was 93.3%. Participants in remission from PTSD after the infusion series (n = 12) had a median time to relapse of 41 days. Similarly, participants whose depression symptoms responded to the infusion series (n = 14) had a median time to relapse of 20 days. Repeated ketamine infusions were associated with transient increases in dissociative symptoms. No participant reported worsening of PTSD symptoms over the study duration. CONCLUSIONS:This study, the first open-label study of repeated ketamine infusions in a comorbid population, found rapid and sustained improvement in PTSD and depression symptoms. This report suggests that repeated ketamine treatments are safe and may represent an efficacious treatment for individuals with comorbid PTSD and TRD. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT02577250. 10.4088/JCP.17m11634
The antidepressant efficacy of subanesthetic-dose ketamine does not correlate with baseline subcortical volumes in a replication sample with major depressive disorder. Journal of psychopharmacology (Oxford, England) BACKGROUND:This study sought to reproduce, in a larger sample, previous findings of a correlation between smaller raw 3-Tesla (3T) hippocampal volumes and improved antidepressant efficacy of ketamine in individuals with major depressive disorder (MDD). A secondary analysis stratified subjects according to functional BDNF rs6265 (val66met) genotype. METHODS:Unmedicated subjects with treatment-resistant MDD ( n=55) underwent baseline structural 3T MRI. Data processing was conducted with FSL/FIRST and Freesurfer software. The amygdala, hippocampus, and thalamus were selected a priori for analysis. All subjects received a single 0.5mg/kg × 40-minute ketamine infusion. Pearson correlations were performed with subcortical volumes and percent change in MADRS score (from baseline to 230 minutes, 1 day, and 1 week post-infusion). RESULTS:Raw and corrected subcortical volumes did not correlate with antidepressant response at any timepoint. In val/val subjects ( n=23), corrected left and right thalamic volume positively correlated with antidepressant response to ketamine at 230 minutes post-infusion but did not reach statistical significance. In met carriers ( n=14), corrected left and right thalamic volume negatively correlated with antidepressant response to ketamine. CONCLUSION:Baseline subcortical volumes implicated in MDD did not correlate with ketamine's antidepressant efficacy. Baseline thalamic volume and BDNF genotype may be a combinatorial rapid antidepressant response biomarker. 10.1177/0269881117732514
Plasma metabolomic profiling of a ketamine and placebo crossover trial of major depressive disorder and healthy control subjects. Moaddel Ruin,Shardell Michelle,Khadeer Mohammed,Lovett Jacqueline,Kadriu Bashkim,Ravichandran Sarangan,Morris Patrick J,Yuan Peixiong,Thomas Craig J,Gould Todd D,Ferrucci Luigi,Zarate Carlos A Psychopharmacology (R,S)-Ketamine produces rapid, robust, and sustained antidepressant effects in major depressive disorder. Specifically, its pharmacological efficacy in treatment refractory depression is considered a major breakthrough in the field. However, the mechanism of action of ketamine's rapid effect remains to be determined. In order to identify pathways that are responsible for ketamine's effect, a targeted metabolomic approach was carried out using a double-blind, placebo-controlled crossover design, with infusion order randomized with medication-free patients with treatment-resistant major depressive disorder (29 subjects) and healthy controls (25 subjects). The metabolomic profile of these subjects was characterized at multiple time points, and a comprehensive analysis was investigated between the following: MDD and healthy controls, treatment and placebo in both groups and the corresponding response to ketamine treatment. Ketamine treatment resulted in a general increase in circulating sphingomyelins, levels which were not correlated with response. Ketamine response resulted in more pronounced effects in the kynurenine pathway and the arginine pathway at 4 h post-infusion, where a larger decrease in circulating kynurenine levels and a larger increase in the bioavailability of arginine were observed in responders to ketamine treatment, suggesting possible mechanisms for response to ketamine treatment. 10.1007/s00213-018-4992-7
Promises and concerns regarding the use of ketamine and esketamine in the treatment of depression. Pérez-Esparza R,Kobayashi-Romero L F,García-Mendoza A M,Lamas-Aguilar R M,Fonseca-Perezamador A Acta psychiatrica Scandinavica 10.1111/acps.13063
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA psychiatry Importance:Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants. Objective:To assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD). Design, Setting, and Participants:This 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. Interventions:In 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 Measures:The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Results:Sixty-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 Relevance:In 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 Registration:clinicaltrials.gov identifier: NCT01998958. 10.1001/jamapsychiatry.2017.3739
Oral esketamine for treatment-resistant depression: rationale and design of a randomized controlled trial. BMC psychiatry BACKGROUND:There is an urgent need to develop additional treatment strategies for patients with treatment-resistant depression (TRD). The rapid but short-lived antidepressant effects of intravenous (IV) ketamine as a racemic mixture have been shown repeatedly in this population, but there is still a paucity of data on the efficacy and safety of (a) different routes of administration, and (b) ketamine's enantiomers esketamine and arketamine. Given practical advantages of oral over IV administration and pharmacodynamic arguments for better antidepressant efficacy of esketamine over arketamine, we designed a study to investigate repeated administration of oral esketamine in patients with TRD. METHODS:This study features a triple-blind randomized placebo-controlled trial (RCT) comparing daily oral esketamine versus placebo as add-on to regular antidepressant medications for a period of 6 weeks, succeeded by a follow-up of 4 weeks. The methods support examination of the efficacy, safety, tolerability, mechanisms of action, and economic impact of oral esketamine in patients with TRD. DISCUSSION:This is the first RCT investigating repeated oral esketamine administration in patients with TRD. If shown to be effective and tolerated, oral esketamine administration poses important advantages over IV administration. TRIAL REGISTRATION:Dutch Trial Register, NTR6161. Registered 21 October 2016. 10.1186/s12888-019-2359-1
Increased Reactivity of the Mesolimbic Reward System after Ketamine Injection in Patients with Treatment-resistant Major Depressive Disorder. Sterpenich Virginie,Vidal Sonia,Hofmeister Jeremy,Michalopoulos Giorgio,Bancila Victor,Warrot Delphine,Dayer Alexandre,Desseilles Martin,Aubry Jean-Michel,Kosel Markus,Schwartz Sophie,Vutskits Laszlo Anesthesiology WHAT WE ALREADY KNOW ABOUT THIS TOPIC:The antidepressant effect of ketamine is associated with increased activity in the reward circuitry of the brain and a suppression of circuitry that mediates perceptual processing of negative emotions. The duration of ketamine effect on these brain structures remains to be defined. WHAT THIS ARTICLE TELLS US THAT IS NEW:As expected, ketamine administration led to an improvement in mood and global vigilance. The improvement in mood was accompanied by an increased recruitment of the orbitofrontal cortex, ventral striatum, medial substantial nigra and ventral tegmental area, structures that are part of the reward circuitry.Responses in the mesolimbic structures (amygdala, medial substantial nigra and ventral tegmental area, orbitofrontal cortex) to negative stimuli were decreased after ketamine administration.The data are consistent with the premise that ketamine induces sustained changes in the mesolimbic neural circuits to reset pathological reward and emotional processing. BACKGROUND:Ketamine rapidly improves maladaptive mood states in major depressive disorder, and some of the neural substrates underlying this therapeutic effect have been identified. This study aimed to identify functional changes within neural networks that may underlie the impact of ketamine on both reward and emotional processing in patients with treatment-resistant major depression. METHODS:Ten adult patients with a Montgomery-Åsberg Depression Rating Scale score above 25 were enrolled to receive a single intravenous administration of ketamine (0.5 mg/kg). Patients' performance along with related neural network activations were analyzed in a game-like reward task and in an emotional judgment task using functional magnetic resonance imaging 1 day before and 1 and 7 days after ketamine administration. RESULTS:A significant correlation (R = 0.46, P = 0.03) between the improvement of depression scores and the enhanced reaction time for positive items was found in the game-like reward task 1 day after ketamine administration. This enhanced sensitivity for rewarded items was accompanied by increased activity of reward-related brain regions, including the orbitofrontal cortex, ventral striatum, and the ventral tegmental area, an effect that persisted up to 1 week after ketamine injection. In the emotional judgment task, it was found that ketamine rapidly modified local brain activities in response to emotionally negative, positive, or neutral stimuli in the amygdala, insula, anterior cingulate cortex, and in the ventral tegmental area. CONCLUSIONS:Single bolus ketamine administration rapidly triggers lasting changes in mesolimbic neural networks to improve pathologic reward and emotional processing in patients with major depressive disorder. 10.1097/ALN.0000000000002667
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). Fedgchin Maggie,Trivedi Madhukar,Daly Ella J,Melkote Rama,Lane Rosanne,Lim Pilar,Vitagliano Dawn,Blier Pierre,Fava Maurizio,Liebowitz Michael,Ravindran Arun,Gaillard Raphael,Ameele Hans Van Den,Preskorn Sheldon,Manji Husseini,Hough David,Drevets Wayne C,Singh Jaskaran B The international journal of neuropsychopharmacology 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. 10.1093/ijnp/pyz039
Esketamine for treatment resistant depression: a trick of smoke and mirrors? Gastaldon C,Papola D,Ostuzzi G,Barbui C Epidemiology and psychiatric sciences 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. 10.1017/S2045796019000751
Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study. Journal of affective disorders BACKGROUND:Ketamine and its enantiomers have recently been highlighted as one of the most effective therapeutic options in refractory depression. However, racemic ketamine and esketamine have not been directly compared. The aim of this study is to assess the efficacy and safety of esketamine compared to ketamine in patients with treatment-resistant depression (TRD). METHODS:This is a randomized, double-blind, active-controlled, bicentre, non-inferiority clinical trial, with two parallel groups. Participants were randomly assigned to a 40-min single intravenous infusion of ketamine 0.5 mg/kg or esketamine 0.25 mg/kg. The primary outcome was the difference in remission rates for depression 24 h following intervention using the Montgomery-Åsberg Depression Rating Scale (MADRS), with a non-inferiority margin of 20%. RESULTS:63 subjects were included and randomly assigned (29 to receive ketamine and 34 to receive esketamine). At 24 h, 24.1% of participants in the ketamine group and 29.4% of participants in the esketamine group showed remission, with a difference of 5.3% (95% CILB -13.6%), confirming non-inferiority. MADRS scores improved from 33 (SD 9.3) to 16.2 (SD 10.7) in the ketamine group and from 33 (SD 5.3) to 17.5 (SD 12.2) in the esketamine one, with a difference of -5.27% (95% CILB, -13.6). Both groups presented similar mild side effects. CONCLUSIONS:Esketamine was non-inferior to ketamine for TRD 24 h following infusion. Both treatments were effective, safe, and well tolerated. TRIAL REGISTRATION:Registered in Japan Primary Registries Network: UMIN000032355. 10.1016/j.jad.2019.11.086
Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study. Popova Vanina,Daly Ella J,Trivedi Madhukar,Cooper Kimberly,Lane Rosanne,Lim Pilar,Mazzucco Christine,Hough David,Thase Michael E,Shelton Richard C,Molero Patricio,Vieta Eduard,Bajbouj Malek,Manji Husseini,Drevets Wayne C,Singh Jaskaran B The American journal of psychiatry OBJECTIVE:About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients with treatment-resistant depression from an ineffective antidepressant to flexibly dosed esketamine nasal spray plus a newly initiated antidepressant or to a newly initiated antidepressant (active comparator) plus placebo nasal spray. METHODS:This was a phase 3, double-blind, active-controlled, multicenter study conducted at 39 outpatient referral centers. The study enrolled adults with moderate to severe nonpsychotic depression and a history of nonresponse to at least two antidepressants in the current episode, with one antidepressant assessed prospectively. Confirmed nonresponders were randomly assigned to treatment with esketamine nasal spray (56 or 84 mg twice weekly) and an antidepressant or antidepressant and placebo nasal spray. The primary efficacy endpoint, change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) score, was assessed by a mixed-effects model using repeated measures. RESULTS:Of 435 patients screened, 227 underwent randomization and 197 completed the 28-day double-blind treatment phase. Change in MADRS score with esketamine plus antidepressant was significantly greater than with antidepressant plus placebo at day 28 (difference of least square means=-4.0, SE=1.69, 95% CI=-7.31, -0.64); likewise, clinically meaningful improvement was observed in the esketamine plus antidepressant arm at earlier time points. The five most common adverse events (dissociation, nausea, vertigo, dysgeusia, and dizziness) all were observed more frequently in the esketamine plus antidepressant arm than in the antidepressant plus placebo arm; 7% and 0.9% of patients in the respective treatment groups discontinued study drug because of an adverse event. Adverse events in the esketamine plus antidepressant arm generally appeared shortly after dosing and resolved by 1.5 hours after dosing. CONCLUSIONS:Current treatment options for treatment-resistant depression have considerable limitations in terms of efficacy and patient acceptability. Esketamine is expected to address an unmet medical need in this population through its novel mechanism of action and rapid onset of antidepressant efficacy. The study supports the efficacy and safety of esketamine nasal spray as a rapidly acting antidepressant for patients with treatment-resistant depression. 10.1176/appi.ajp.2019.19020172
Efficacy and safety of intranasal esketamine for the treatment of major depressive disorder. Kryst Joanna,Kawalec Paweł,Pilc Andrzej Expert opinion on pharmacotherapy : In March 2019, intranasal esketamine was approved by the Food and Drug Administration (FDA) for the treatment of treatment-resistant depression (TRD) in adults. This review presents the results of clinical trials underlying the FDA approval of intranasal esketamine.: Esketamine's efficacy and safety in TRD were assessed in 5 phase III studies: three 4-week, placebo-controlled studies, and two long-term trials. One short-term trial showed statistically significant antidepressant effects of esketamine vs placebo, while a long-term withdrawal study showed that esketamine is significantly beneficial in terms of extending time to relapse, compared to placebo. Two other short-term trials did not meet the prespecified statistical tests for showing efficacy, although improvement in depressive symptoms from baseline to the end of week 4 favors esketamine over placebo.: Intranasal esketamine is a new treatment option for people with TRD. The main benefit of esketamine is rapid onset of antidepressant activity, but the effects of prolonged treatment are still preliminary. The main concerns relate to the safety aspects of prolonged esketamine therapy, when considering its abuse potential. While data for esketamine use over a long period of time is lacking, its use should be carefully monitored. 10.1080/14656566.2019.1683161
Comparative study of esketamine and racemic ketamine in treatment-resistant depression: Protocol for a non-inferiority clinical trial. Medicine INTRODUCTION:The use of ketamine as an option in the treatment of depressive disorder is growing rapidly, supported by numerous clinical trials attesting its efficacy and safety. Esketamine, the S (+) enantiomer of ketamine, is the most widely used form in the anesthetic environment in some countries, and new studies have shown that it may also be effective in depression and with better tolerability. However, no study so far has directly compared esketamine with racemic ketamine. Here we propose a protocol of a clinical trial to evaluate esketamine as a noninferior medication when compared to ketamine in the treatment of patients with treatment-resistant depression. METHODS/DESIGN:This study protocol is for a randomized, controlled, double-blind noninferiority clinical trial. Subjects will be 18 years or older, with major depression characterized as treatment-resistant. Participants will receive a single infusion of either esketamine (0.25 mg/kg) or ketamine (0.5 mg/kg) over 40 minutes. The primary outcome will be the difference in remission rates between the 2 treatment arms at 24 and 72 hours after drug infusion. Secondary outcomes will include other timepoints, measurements of cognition, dissociation, and blood biomarkers. DISCUSSION:A head-to-head study is the best way to evaluate whether the esketamine is in fact comparable to the racemic ketamine in terms of both efficacy and safety, and, if positive, it would be an initial step to increase the access to that type of treatment worldwide. ETHICS AND DISSEMINATION:The study was approved by the local Institutional Review Board (University Hospital Professor Edgard Santos-Federal University of Bahia-Number: 46657415.0.0000.0049). Subjects will only participate after voluntarily agreeing and signing the Informed Consent Form. The study findings will be published in peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION:This trial has been registered in the Japan Primary Registries Network (JPRN): UMIN000032355, which is affiliated with the World Health Organization. 10.1097/MD.0000000000012414