Clinical Question: Brief description of patient problem/setting (summarize the case very briefly)
A 32 year old Asian female is BIBEMS for active suicidal ideation with a recent suicidal attempt. The patient has a history of MDD and has been admitted for similar episodes multiple times in the past 5 years. Pt endorses that she is compliant with her medications and has routine follow ups with outpatient psychology. During the interview she states that medications have never worked for her and that she has “tried it all”. At the time of interview, she was still actively suicidal. Is this patient a candidate for treatment with nasal esketamine?
PICO Question: Clearly state the question (including outcomes or criteria to be tracked)
In patients with treatment resistant depression would utilization of nasal esketamine spray improve depression and suicidal ideation?
PICO search terms:
| P | I | C | O |
| Treatment resistant depressed adults | Nasal Esketamine | Usual/No Treatment | Improvement in depression/suicidal ideation |
Search tools and strategy used:
Please indicate what data bases/tools you used, provide a list of the terms you searched together in each tool, and how many articles were returned using those terms and filters.
| Database | Terms | Filter | Articles |
| Wiley Online Library | esketamine nasal spray for treatment resistant depression | JournalsLast 5 YearsFull Access | 44 |
| Cochrane Library (Wiley) | esketamine nasal spray for treatment resistant depression | Last 2 years | 36 |
| PubMed | esketamine nasal spray for treatment resistant depression | Clinical TrialReviewLast 5 YearsHumansFree Full Text | 14 |
| JAMA | esketamine nasal spray for treatment resistant depression | ReviewResearchCase Report | 9 |
| ScienceDirect | esketamine nasal spray for treatment resistant depression | Last 10 YearsReview ArticlesOpen Access | 22 |
| Google Scholar | esketamine nasal spray for treatment resistant depression | Since 2017; Sort by Relevance | 209 |
Results found: 334
Explain how you narrow your choices to the few selected articles.
This is an area of extremely focused research with limited but strong forms of data available to answer the PICO question. During my research, I needed to peruse through the results to find those related to treatment resistant depression and those that studied the utilization of microwave technology that I was interested in. Usually, Google Scholar recommends thousands of articles for other search questions however this search only yielded 209 results, unfortunately many of them are not entirely relevant to my search. A total of 5 articles were considered for inclusion. These articles were found from various databases as listed above. These articles were initially selected by assessing the abstract to ensure that they met the criteria of my PICO question.
Articles Chosen:
| CITATION | Ionescu DF, Fu DJ, Qiu X, et al. 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). Int J Neuropsychopharmacol. 2021;24(1):22-31. doi:10.1093/ijnp/pyaa068 |
| 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. |
| LINK/PDF | See BlackBoard Post. |
| CITATION | Fu DJ, Ionescu DF, Li X, et al. 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). J Clin Psychiatry. 2020;81(3):19m13191. Published 2020 May 12. doi:10.4088/JCP.19m13191 |
| 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. |
| LINK/PDF | See BlackBoard Post. |
| CITATION | Fedgchin M, Trivedi M, Daly EJ, et al. 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). Int J Neuropsychopharmacol. 2019;22(10):616-630. doi:10.1093/ijnp/pyz039 |
| 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. |
| LINK/PDF | See BlackBoard Post. |
| CITATION | Daly EJ, Singh JB, Fedgchin M, et al. Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. 2018;75(2):139-148. doi:10.1001/jamapsychiatry.2017.3739 |
| ABSTRACT | 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. |
| LINK/PDF | See BlackBoard Post. |
| CITATION | Jiaqi Xiong, Orly Lipsitz, David Chen-Li, Joshua D. Rosenblat, Nelson B. Rodrigues, Isabelle Carvalho, Leanna M.W. Lui, Hartej Gill, Flora Narsi, Rodrigo B. Mansur, Yena Lee, Roger S. McIntyre, The acute antisuicidal effects of single-dose intravenous ketamine and intranasal esketamine in individuals with major depression and bipolar disorders: A systematic review and meta-analysis, Journal of Psychiatric Research, Volume 134, 2021 |
| ABSTRACT | Objective: The efficacy of ketamine in reducing suicidal ideation (SI) has been previously reported. We aimed to evaluate acute anti-SI effects of single-dose ketamine in different formulations/routes of administration by pooling results from randomized controlled trials (RCTs). A systematic search was conducted on Cochrane, Embase, Medline, and PubMed from inception to July 1st, 2020.Methods: Studies were selected based on pre-determined eligibility criteria. Effect sizes of different formulations/routes at various time points were computed using random-effects models. With data from nine eligible RCTs (n = 197), the pooled effect size for anti-SI effects at the 24-h time point was 1.035 (N = 6, CI: 0.793 to 1.277, p < 0.001) for intravenous (IV) racemic ketamine and 1.309 (N = 1, CI: 0.857 to 1.761, p < 0.001) for intranasal (IN) esketamine. An additional five RCTs were available for qualitative analysis. RCTs were identified for oral/sublingual ketamine for depression, however, none of these trials reported anti-SI effects preventing quantitative analysis for these routes of delivery. No RCTs for intramuscular (IM) ketamine were identified.Conclusion: The findings suggest that single-dose IV ketamine/IN esketamine is associated with robust reductions in suicidal thoughts at 2-h, 4-h, and 24-h post-intervention. In addition, future studies on IM/oral/sublingual ketamine and comparative studies are warranted to evaluate the anti-SI efficacy of distinct formulations and routes of administration. |
| LINK/PDF | See BlackBoard Post. |
Summary of the Evidence:
| Author (Date) | Level of Evidence | Sample/Setting (# of subjects/ studies, cohort definition etc. ) | Outcome(s) studied | Key Findings | Limitations and Biases |
| Dawn F. Ionescu, Dong-Jing Fu, Xin Qiu, Rosanne Lane, Pilar Lim, Siegfried Kasper, David Hough, Wayne C. Drevets, Husseini Manji, Carla M. Canuso (2021) | Double Blind Randomized Control Trial | Eligible patients were between 18 and 64 years of age, met the Diagnostic and Statistical Manual of Mental Disorders–5th edition Key exclusion criteria were selected concurrent psychiatric illnesses; moderate to severe substance or alcohol use disorder within 6 months prior to screening; current or prior diagnosis of psychotic disorder; and positive urine test result(s) for phencyclidine, cocaine, or amphetamines unless patients were on prescription psychostimulant(s) treatmentStudy comprised 3 phases: (1) a screening phase/visit performed within 48 hours before the first dose of intranasal study drug to assess patients’ eligibility for study enrollment, (2) a 25-day double-blind treatment phase, and (3) a 9-week follow-up phase (days 26–90).Of the 230 patients, 184 completed double blind treatment and were given esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks | Utilized the Montgomery-Asberg Depression Rating Scale and the Clinical Global Impression-Severity of Suicidality-revised to determine baseline depression and suicidality. Analysis of Covariance was used to determine the efficacy of nasal esketamine on both of these factors 24 hours after treatment.Patients were noted to have a rapid reduction in Clinical Global Impression-Severity of Suicidality-revised score after treatment | MADRS total score decreased from baseline to 24 hours after the first doseThe advantage with esketamine continued until the end of 4-week double-blind treatment (LS mean treatment difference ranging from –1.2 to –3.7, statistically significant at day 25 predose)No completed suicides were observed in either treatment groupPatients in both treatment groups experienced rapid reduction in the severity of their suicidality as measured by the CGI-SS-r | There is a dissociative effect associated with ketamine, this leads to challenges conducting a safe and ethical trial, 3 patients attempted suicide in this trialNeed to weigh out the possibility of a placebo affect with trials involving a new psychiatric drug Patients were in multiple hospital systems in many different regions, each patient experienced a different duration of inpatient hospitalization |
| Dong-Jing Fu, Dawn F. Ionescu, Xiang Li, Rosanne Lane, Pilar Lim, Gerard Sanacora, David Hough, Wayne C. Drevets, Husseini Manji, Carla M. Canuso (2020) | Double Blind Randomized Control Trial | Eligible patients were between 18 and 64 years of age, met the Diagnostic and Statistical Manual of Mental Disorders–5th edition Key exclusion criteria were selected concurrent psychiatric illnesses; moderate to severe substance or alcohol use disorder within 6 months prior to screening; current or prior diagnosis of psychotic disorder; and positive urine test result(s) for phencyclidine, cocaine, or amphetamines unless patients were on prescription psychostimulant(s) treatmentIncluded adults diagnosed with MDD and having active suicidal ideation, with current need for psychiatric hospitalization as well as newly initiated or optimized oral antidepressant therapy | 226 patients completed double blind treatment and were given esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks.Utilized the Montgomery-Asberg Depression Rating Scale and the Clinical Global Impression-Severity of Suicidality-revised to determine baseline depression and suicidality. Analysis of Covariance was used to determine the efficacy of nasal esketamine on both of these factors 24 hours after treatment and throughout the 4 weeks. | Patients were noted to have a rapid reduction in Clinical Global Impression-Severity of Suicidality-revised score after treatmentAt 24 hour endpoint patients in both treatment groups had marked improvement in suicidality by measurement of CGI-rrTreatment effect of esketamine on depressive symptoms was observed after 4 hours | Need to weigh out the possibility of a placebo affect with trials involving a new psychiatric drug Esurance of ethical practice and patient safetytransient, dissociative effects observed with esketamine that could potentially cause functional unblinding of site staff |
| Maggie Fedgchin, Madhukar Trivedi, Ella J. Daly, Rama Melkote, Rosanne Lane, Pilar Lim, Dawn Vitagliano, Pierre Blier, Maurizio Fava, Michael Liebowitz, Arun Ravindran, Raphael Gaillard, Hans van den Ameele, Sheldon Preskorn, Husseini Manji, David Hough, Wayne C. Drevets, Jaskaran B. Singh (2019) | Double Blind Randomized Control Trial | Multicenter study was conducted in outpatient centers between September 2015 and February 2018Patients were between 18 and 64 years of age with recurrent MDD or single-episode MDD (≥2 years), without psychotic featuresKey exclusion criteria were suicidal ideation with intent to act within the prior 6 months or suicidal behavior within the prior year; diagnosis of psychotic disorder, bipolar or related disorders; recent history (within prior 6 months) of moderate or severe substance use disorder; and, positive test result(s) for specified drugs of abuse | MADRS assessments were performed as primary and secondary efficacy evaluationsAll MADRS assessments were performed via telephone by independent raters who were blinded to the protocol detailsRated overall change in severity of depressive illness using the Clinical Global Impression-Severity, Sheehan Disability Scale, Generalized Anxiety Disorder 7-itemPrimary efficacy endpoint, change from baseline (day 1) to day 28 in MADRS total score, was analyzed using a mixed-effects repeated measures model | Most randomized patients (315/346, 91.0%) completed the double-blind phaseTreatment differences at day 28 of –3.2 and –4.1 for the esketamine 84 mg/ antidepressant and esketamine 56 mg/antidepressant groups, respectively, appear consistent with the positive findings in a similarResponse and remission rates, and subgroup analyses of the primary endpoint, assessed from both the clinician and patient perspective, were also all consistent with the primary endpoint analyses in that the results numerically favored both esketamine/antidepressant groups over antidepressant/placebo. | Need to weigh out the possibility of a placebo affect with trials involving a new psychiatric drug transient, dissociative effects observed with esketamine that could potentially cause functional unblinding of site staff |
| Ella J. Daly, MD; Jaskaran B. Singh, MD; Maggie Fedgchin, PharmD; Kimberly Cooper, MS; Pilar Lim, PhD; Richard C. Shelton, MD; Michael E. Thase, MD; Andrew Winokur, MD, PhD; Luc Van Nueten, MD; Husseini Manji, MD, FRCPC; Wayne C. Drevets, MD (2018) | Double Blind Randomized Control Trial | Enrolled patients aged 20-64 years with a diagnosis of MDDEligible participants had a score of 34 or more on the 30-item, clinician-rated Inventory of Depressive Symptomatology corresponding to moderate to severe depressionExclusion criteria included recent or current suicidal ideation with intent to act, suicidal behavior, or homicidal ideation or intent, diagnosis of bipolar or related disorders, intellectual disability, psychotic disorder, MDD with psychosis, posttraumatic stress disorder, obsessive-compulsive disorder, substance/ alcohol use disorders in the past year, and recent use of cannabis | The duration of each period in the double-blind phase was 1 week, during which time it was expected that efficacy could be achieved. This design allowed evaluation of the dose(s) needed to proceed to evaluation in phase 367 patients participated in a double blind trial, 33 were given a placebo, 11 were given 28 mg of esketamine, 11 were given 56 mg, and 12 were given 84 mg. Then of the 33 given a placebo, another double blind trial was done and 28 participants were split evenly into similar groups as aboveLeast square means analysis of the reported Montgomery-Asberg Depression Rating Scale scores was used to determine the efficacy of intervention in both trials The Montgomery-Asberg Depression Rating Scale scores indicated superior results in patients given esketamine compared to placebo. | The mean MADRS total score decreased from baseline to day 8 in period 1 and from day 8 to day 15 in period 2 in all groups, with greater improvement in all esketamine dose groups compared with placeboMean decrease in the MADRS total score was greater in each esketamine dose group compared with placebo at day 15, with the magnitude of decrease directly related to doseProportion of responders in each esketamine dose group was numerically higher than in the placebo group at the period 2 end point. | Need to weigh out the possibility of a placebo effect with trials involving a new psychiatric drug limited by the small sample size and enrollment criteriaDifficulty blinding esketamine, despite adding a bittering agent to placebo to mimic the taste of esketamine |
| Jiaqi Xiong, Orly Lipsitz, David Chen-Li, Joshua D. Rosenblat, Nelson B. Rodrigues, Isabelle Carvalho, Leanna M.W. Lui, Hartej Gill, Flora Narsi, Rodrigo B. Mansur, Yena Lee, Roger S. McIntyre (2021) | Systematic Review | Systematically searched PubMed, Medline, Embase, and Cochrane databases from inception date to July 1st, 2020Randomized, placebo-controlled, and double-blinded clinical trials that assessed SI within 24-h after single-dose ketamine administration were eligible for inclusion. | Mean differences between baseline and endpoint mean scores or pre- and post-intervention scores in SI measures were obtained/calculated from each study.All statistical analyses were performed on Comprehensive Meta Analysis 2.0 & 3.0 Effect sizes were computed using pre- and post-intervention mean scores.A random-effects model was used for pooling effect sizes considering a potentially high-degree of between-study heterogeneityStudy bias assessment was conducted using the Cochrane risk-of-bias tool for randomized trials independently | Established the acute anti-SI effects of single-dose IV racemic ketamine/IN esketamine in patients with affective disorders with the large and significant effect sizes computed from nine RCTs comprising 197 ketamine-treated patientsSingle dose of esketamine has rapid acute effects in reducing suicidal ideation.Future research on the anti-SI efficacy of formulations of ketamine is needed.Dosages and routes of administration are factors to be considered for optimizing suicidal ideation treatment using ketamine. | Need to weigh out the possibility of a placebo affect with trials involving a new psychiatric drug. Study sample size was small (9), a larger one should be done in the future |
Conclusion(s):
– Briefly summarize the conclusions of each article, then provide an overarching conclusion.
- Dawn F. Ionescu, Dong-Jing Fu, Xin Qiu, Rosanne Lane, Pilar Lim, Siegfried Kasper, David Hough, Wayne C. Drevets, Husseini Manji, Carla M. Canuso (2021): Esketamine plus standard of care resulted in a significant improvement of depressive symptoms compared with placebo plus standard of care. Rapid improvement in depressive symptoms was observed at 4 hours after the first dose, and improvement was maintained until the end of 4-week double-blind treatment.
- Dong-Jing Fu, Dawn F. Ionescu, Xiang Li, Rosanne Lane, Pilar Lim, Gerard Sanacora, David Hough, Wayne C. Drevets, Husseini Manji, Carla M. Canuso (2020): Patients were noted to have a rapid reduction in Clinical Global Impression-Severity of Suicidality-revised score after treatment.
- Maggie Fedgchin, Madhukar Trivedi, Ella J. Daly, Rama Melkote, Rosanne Lane, Pilar Lim, Dawn Vitagliano, Pierre Blier, Maurizio Fava, Michael Liebowitz, Arun Ravindran, Raphael Gaillard, Hans van den Ameele, Sheldon Preskorn, Husseini Manji, David Hough, Wayne C. Drevets, Jaskaran B. Singh (2019): Patients had a 3x treatment withdrawal rate from the 84 mg dosage of nasal esketamine after the first few doses than they did with the 56 mg dosage of nasal esketamine. Researchers argue that this is not significant, and that there seem to be no concerns with lowering the dose. However, was the primary reason why in this trial there was not a statistically significant change at 28 weeks for patients on 84 mg of nasal esketamine, but there was a significant result for those on the 56 mg dosage. The researchers conclude that clinician and patient perspectives both indicate that this therapy is effective compared to the control.
- Ella J. Daly, MD; Jaskaran B. Singh, MD; Maggie Fedgchin, PharmD; Kimberly Cooper, MS; Pilar Lim, PhD; Richard C. Shelton, MD; Michael E. Thase, MD; Andrew Winokur, MD, PhD; Luc Van Nueten, MD; Husseini Manji, MD, FRCPC; Wayne C. Drevets, MD (2018): Demonstrated a dose-independent improvement of depression when nasal ketamine is added to a pre-existing oral antidepressant which is sustained for 2 months.
- Jiaqi Xiong, Orly Lipsitz, David Chen-Li, Joshua D. Rosenblat, Nelson B. Rodrigues, Isabelle Carvalho, Leanna M.W. Lui, Hartej Gill, Flora Narsi, Rodrigo B. Mansur, Yena Lee, Roger S. McIntyre (2021): Single-dose of esketamine has rapid acute effects in reducing suicidal ideation. Further research is needed to identify the optimal dosages and routes of administration.
Clinical Bottom Line:
PICO Question: In patients with treatment resistant depression would utilization of nasal esketamine spray improve depression and suicidal ideation?
Clinical Bottom Line: The highest quality of available and accessible evidence suggests that in patients with treatment resistant depression the addition of nasal esketamine to preexisting oral antidepressant therapy leads to a rapid reduction in symptoms of depression and suicidal ideation, especially in hospitalized patients.
Weight of the Evidence (With Rank (bolded number) and Explanation):
1 Jiaqi Xiong, Orly Lipsitz, David Chen-Li, Joshua D. Rosenblat, Nelson B. Rodrigues, Isabelle Carvalho, Leanna M.W. Lui, Hartej Gill, Flora Narsi, Rodrigo B. Mansur, Yena Lee, Roger S. McIntyre (2021): I weighted this paper to be of the highest evidence because it was a very recently published systematic review that investigated large and significant effect sizes computed from nine RCTs with a total of 197 ketamine-treated patients.
2 Dawn F. Ionescu, Dong-Jing Fu, Xin Qiu, Rosanne Lane, Pilar Lim, Siegfried Kasper, David Hough, Wayne C. Drevets, Husseini Manji, Carla M. Canuso (2021): This is a double blind randomized control trial from 2021. I chose this article because it was of high grade of evidence. It looks critically into the efficacy of nasal esketamine on an inpatient population with MDD and suicidal ideation with active intent. As a double blind RCT it reduces potential biases from those giving and receiving the actual medication. Given the nature of the patient population, I can argue that although the sample population of 184 could be larger, the researchers have recruited a good number of recruits from this niche population. In the future a systematic review of multiple studies might strengthen the association between nasal esketamine and rapid reduction of depression with active suicidal ideation.
3 Maggie Fedgchin, Madhukar Trivedi, Ella J. Daly, Rama Melkote, Rosanne Lane, Pilar Lim, Dawn Vitagliano, Pierre Blier, Maurizio Fava, Michael Liebowitz, Arun Ravindran, Raphael Gaillard, Hans van den Ameele, Sheldon Preskorn, Husseini Manji, David Hough, Wayne C. Drevets, Jaskaran B. Singh (2019): This is a high grade double blind RCT that was published in October of 2019. I rated this lower than the one above of time of publishing. I rated higher than Dong et al because of its sample size. This article had the largest sample size of all the trials mentioned in this mini-CAT. Furthermore, as a double-blind trial, it had minimal interventional biases. Unlike the above 2 RCTs, this article looked critically into the efficacy of different doses of nasal esketamine on patients with treatment resistant depression. The results are very consistent to the other RCTs.
4 Dong-Jing Fu, Dawn F. Ionescu, Xiang Li, Rosanne Lane, Pilar Lim, Gerard Sanacora, David Hough, Wayne C. Drevets, Husseini Manji, Carla M. Canuso (2020): This is a recently published, 2020, phase 3 double blind that is of high-grade evidence with objective results with minimal interventional biases. This article looked critically into the efficacy of nasal esketamine on a hospitalized inpatient population with MDD and suicidal ideation with active intent. The sample size of this RCT is comparable to the one by Dawn et al. Both RCTs (Dawn et al and Fu et al) utilized the same measuring parameters and the results were very consistent.
5 Ella J. Daly, MD; Jaskaran B. Singh, MD; Maggie Fedgchin, PharmD; Kimberly Cooper, MS; Pilar Lim, PhD; Richard C. Shelton, MD; Michael E. Thase, MD; Andrew Winokur, MD, PhD; Luc Van Nueten, MD; Husseini Manji, MD, FRCPC; Wayne C. Drevets, MD (2018): I rated this article as the lowest because it is a clinical randomized control trial that was published in February 2018. However, it contained multiple split double-blind trials and demonstrated a dose-independent improvement of depression when nasal ketamine is added to a pre-existing oral antidepressant. Unlike the other RCTs above this trial also demonstrated that improvements are sustained for 2 months, however this length of effect was not something that was measured in more recent trials.
Magnitude of Effects:
All forms of evidence in the 4 articles discussed thus far demonstrate a high degree of efficacy and safety in use of intranasal ketamine.
Clinical Significance:
Nasal Esketamine is a relatively old medication that was re-introduced recently for possible use in treatment resistant depression. According to the above, multiple double blind randomized control trials have demonstrated that addition of nasal esketamine to preexisting oral antidepressant therapy leads to a rapid reduction in symptoms of depression and suicidal ideation, especially in hospitalized patients. According to the above RCTs there might also be a significant reduction in suicidal ideation, with immediate effect in as little as 4 hours. Daly et al indicate that remission of depression with concomitant use of nasal esketamine with oral antidepressants can be sustained for up to 2 months. Further research is required however there is significant data pointing towards use of esketamine in acute suicidal ideation and in maintenance.
Other Considerations:
The next step in evaluating the efficacy of intranasal ketamine are more systematic reviews to statistically interpret the evidence of RCTs and cohort studies. This would offer a higher grade of evidence and address the sample size issues that the above studies had. A meta-analysis would illuminate the presence of any confounding variables and biases that might be influencing the data. Future research should focus on following a cohort of treated patients for a period of time and observing for long term remission of attempted suicides. The medication is promising but a good long term study can shed light on any possible placebo effect that might be associated with a new drug. One would also need to look into the possible dissociative effects and “ego death” with certain doses of Ketamine and how that might influence the decrease in suicidal ideation.
