TLDR: Esketamine nasal spray, combined with standard antidepressant therapy, significantly improves remission rates and reduces time to remission in adults with major depressive disorder (MDD) and acute suicidality compared to standard care alone.
Highlights:
- Remission Rates: Patients treated with esketamine plus standard of care had higher remission rates than those treated with placebo plus standard of care.
- Time to Remission: Esketamine treatment significantly shortened the median time to remission (15 days vs. 23 days) and consistent remission (23 days vs. 50 days) compared to placebo.
- Proportion in Remission: By day 25, a greater proportion of patients in the esketamine group achieved remission (65.2% vs. 55.5%) and consistent remission (54.2% vs. 39.8%) compared to the placebo group.
- Days in Remission: During the double-blind treatment phase, patients in the esketamine group spent a significantly greater percentage of days in remission (27.1% vs. 8.3%).
- Sustained Effect: The clinical benefits of esketamine treatment were maintained during the follow-up phase, even after discontinuation of esketamine.
Source: BMC Psychiatry (2023)
Esketamine: A Novel Treatment for Major Depression and Suicidality
Esketamine is a nasal spray medication developed as a rapid-acting antidepressant for adults with major depressive disorder (MDD) who experience acute suicidal ideation or behavior.
It is the S-enantiomer of ketamine, a well-known anesthetic with rapid antidepressant effects.
Esketamine is marketed under the brand name SPRAVATO® and was approved by the U.S. Food and Drug Administration (FDA) in 2020 for its use in conjunction with oral antidepressant therapy.
Mechanism of Action
Unlike traditional antidepressants that primarily affect serotonin, norepinephrine, and dopamine pathways, esketamine functions through a different mechanism:
- NMDA Receptor Antagonist: Esketamine blocks the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptor in the brain. This blockade leads to increased glutamate release, which enhances synaptic plasticity and connectivity.
- Rapid Symptom Relief: By modulating glutamatergic transmission, esketamine induces rapid changes in the brain that contribute to its quick antidepressant effects, often noticeable within hours of administration.
Efficacy for MDD
Esketamine’s unique mechanism and rapid action make it particularly effective for patients with severe depression and suicidality:
- Rapid Onset: Esketamine can significantly reduce depressive symptoms within 24 hours, offering a critical intervention for those at imminent risk of suicide.
- Treatment-Resistant Depression: It has shown efficacy in individuals who have not responded to multiple other antidepressant therapies, providing a new option for these challenging cases.
- Sustained Benefits: Clinical trials, including the ASPIRE I and II studies, have demonstrated that esketamine, when used with standard care, leads to higher remission rates and more sustained remission compared to placebo.
How Esketamine May Be Useful
Acute Intervention: For patients with MDD and acute suicidal ideation, traditional antidepressants can take weeks to become effective. Esketamine offers a rapid intervention, bridging the gap until longer-term treatments take effect.
Enhanced Synaptic Plasticity: By enhancing synaptic connectivity, esketamine helps restore normal brain function more quickly than traditional antidepressants.
Complementary Treatment: When used alongside oral antidepressants, esketamine can provide both immediate and long-term relief, addressing both the acute and chronic aspects of depression and suicidality.
Major Findings: Esketamine for Severe Depression (2023 Study)
1. Time to Remission
Significantly Shorter Time: Patients treated with esketamine plus standard of care (SOC) reached remission significantly faster than those treated with placebo plus SOC. The median time to achieve remission, defined as a Montgomery-Åsberg Depression Rating Scale (MADRS) total score of ≤12, was 15 days for the esketamine group compared to 23 days for the placebo group (p = 0.005).
Consistent Remission: The median time to consistent remission (two consecutive visits with a MADRS total score of ≤12) was also significantly shorter for the esketamine group, with 23 days compared to 50 days for the placebo group (p = 0.007).
2. Proportion of Patients Achieving Remission
Higher Remission Rates: By day 25, a greater proportion of patients in the esketamine group achieved remission compared to the placebo group. Specifically, 65.2% of patients in the esketamine group achieved remission versus 55.5% in the placebo group.
Consistent Remission Rates: For consistent remission, 54.2% of patients in the esketamine group achieved this endpoint by day 25 compared to 39.8% in the placebo group.
3. Days in Remission
More Total Days: During the double-blind treatment phase, patients treated with esketamine spent a significantly greater percentage of days in remission compared to those receiving placebo. Specifically, the esketamine group spent 27.1% of days (approximately 5 days) in remission, whereas the placebo group spent only 8.3% of days (approximately 2 days) in remission (p = 0.006).
Sustained Remission: This significant difference in the percentage of days spent in remission was maintained during the follow-up phase, indicating sustained benefits from esketamine treatment even after its discontinuation.
4. Combined Endpoint Analysis
Enhanced Outcomes: When using a combined endpoint of MADRS total score ≤ 12 and Clinical Global Impression-Severity of Suicidality-revised version (CGI-SS-r) ≤ 1 (not suicidal/questionably suicidal), esketamine treatment showed similar significant benefits in terms of both time to remission and the proportion of patients achieving remission.
Study Details: Post Hoc Analysis of Esketamine Nasal Spray in Depression (2023)
The aim of this post hoc analysis was to assess the effect of esketamine nasal spray combined with standard of care (SOC) versus placebo plus SOC on remission-related endpoints in adults with major depressive disorder (MDD) and acute suicidal ideation or behavior.
Methods
- Study Design: The analysis used pooled data from two double-blind, randomized, placebo-controlled, multicenter phase 3 studies: ASPIRE I and ASPIRE II.
- Participants: A total of 451 patients with moderate to severe MDD and acute suicidal ideation or behavior were included.
- Treatment: Patients were randomized to receive esketamine (84 mg) or placebo nasal spray twice weekly, in addition to SOC which included initial psychiatric hospitalization and oral antidepressant therapy.
- Endpoints: Remission was defined as a MADRS total score ≤ 12 at any visit, and consistent remission was defined as a MADRS total score ≤ 12 for two consecutive visits. Combined endpoints incorporating CGI-SS-r ≤ 1 were also evaluated.
Limitations
- Post Hoc: The analysis was post hoc, which can introduce bias and limits the ability to establish causality.
- Multiple Comparisons: No adjustment was made for multiple comparisons, which increases the risk of Type I errors.
- Assessment Intervals: The intermittent nature of MADRS and CGI-SS-r assessments means that remission status between visits was estimated using the last observation carried backward, which may not reflect continuous remission.
Potential Applications & Implications
Rapid Treatment: Esketamine nasal spray can be used as a rapid-acting treatment for patients with MDD and acute suicidality, providing immediate symptom relief.
Hospital Settings: Given its fast-acting nature, esketamine can be particularly useful in emergency psychiatric settings and for inpatients requiring urgent intervention.
Standard of Care Integration: Esketamine offers an effective addition to the current standard of care, potentially reducing the need for prolonged hospitalization and allowing for quicker stabilization of patients.
Guideline Revisions: The findings may influence clinical guidelines to incorporate esketamine as a recommended treatment for MDD with acute suicidality.
How to Get Esketamine for Depression
- Consult a Psychiatrist: Schedule an appointment with a psychiatrist to discuss your symptoms and treatment options.
- Evaluation: Undergo a thorough evaluation to determine if you meet the criteria for esketamine treatment (severe MDD with acute suicidal ideation).
- Referral: If eligible, your psychiatrist can refer you to a certified treatment center that administers esketamine.
- Treatment Plan: The treatment center will develop a plan that includes esketamine nasal spray in conjunction with ongoing oral antidepressant therapy.
- Monitoring: Esketamine is administered under medical supervision due to its potential side effects and the need for monitoring.
Conclusion: Esketamine is a Promising Antidepressant
Esketamine nasal spray has emerged as a promising treatment for adults with major depressive disorder (MDD) and acute suicidal ideation, offering rapid and sustained relief from severe depressive symptoms.
The ASPIRE I and II studies demonstrated that esketamine, when combined with standard of care, significantly shortens the time to remission, increases remission rates, and enhances the duration of remission compared to placebo.
These findings highlight the potential of esketamine to fill a critical gap in the treatment of MDD with suicidality, where rapid intervention is essential.
Despite the limitations of the post hoc analysis, the robust and consistent results support the integration of esketamine into clinical practice for high-risk patients.
Accessing esketamine involves consulting with a psychiatrist, undergoing evaluation, and receiving treatment at a certified center.
The implications of this research extend beyond individual patient care, suggesting potential updates to clinical guidelines and treatment protocols.
Overall, esketamine represents a significant advancement in the management of severe depression and suicidality, offering new hope for people with refractory depression.
References
- Study: Esketamine versus placebo on time to remission in major depressive disorder with acute suicidality (2023)
- Authors: Dong-Jing Fu et al.
