What is the efficacy of esketamine (generic name) for treatment-resistant depression?

Efficacy of Esketamine for Treatment-Resistant Depression

Esketamine nasal spray is effective for treatment-resistant depression (TRD), significantly improving depressive symptoms and remission rates when used as augmentation therapy with oral antidepressants in patients who have failed at least two previous adequate antidepressant trials. 1

Mechanism and Efficacy Evidence

Esketamine is the S-enantiomer of racemic ketamine and works as a non-selective, non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor 2. Its antidepressant mechanism, while not fully understood, involves rapid modulation of glutamatergic neurotransmission.

The 2022 VA/DoD Clinical Practice Guideline provides strong evidence supporting esketamine's efficacy:

• A meta-analysis of 5 RCTs demonstrated that twice-weekly dosing of esketamine as augmentation to ongoing oral antidepressant use improved depressive symptoms and remission rates in TRD patients at up to 28 days of follow-up 1
• These benefits were specifically observed in patients with TRD and those with new or optimized antidepressant therapy
• Significant improvement in depressive symptoms occurs rapidly, often within 24 hours of administration 1

Efficacy in Specific Populations

For TRD Patients:

• Most effective when used as augmentation therapy with standard antidepressants
• Particularly beneficial for patients who have failed at least two adequate trials of antidepressants
• Shows rapid onset of action compared to conventional antidepressants

For Patients with Suicidal Ideation:

• Esketamine is FDA-approved for treating depressive symptoms in adults with MDD and acute suicidal ideation or behavior
• However, its effectiveness in preventing suicide or reducing suicidal ideation long-term has not been definitively established 1
• Studies show particular benefit in patients with a history of suicide attempt, with significant improvement in Clinical Global Impression-Severity of Suicidality-Revised scores at 24 hours 3

Administration and Dosing

Esketamine is administered as a nasal spray:

• Typical dosing ranges from 28mg to 84mg
• Administered twice weekly during initial treatment phase
• Requires monitoring for 2 hours after administration due to risk evaluation and mitigation strategy requirements 1
• Must be used in conjunction with an oral antidepressant for optimal efficacy

Limitations and Considerations

Despite its efficacy, several important limitations should be considered:

• Short-term vs. Long-term Efficacy: While evidence supports longer-term maintenance use, most studies focus on short to medium-term outcomes (up to 28 days) 1
• Patient Selection: Not recommended as initial treatment but reserved for patients who have failed previous therapies or cannot tolerate them 1
• Safety Monitoring Requirements: Unlike ketamine, esketamine has strict risk evaluation and mitigation strategy requirements, including:
  • Pharmacy and healthcare setting certification
  • Mandatory 2-hour monitoring after treatment
  • Restrictions on driving and operating machinery until the next day 2

Common Side Effects

The most common adverse effects (≥5% and at least twice that of placebo) include:

• Dissociation
• Dizziness
• Nausea
• Sedation
• Vertigo
• Hypoesthesia
• Anxiety
• Blood pressure increases
• Vomiting 2

Clinical Algorithm for Use

1. Confirm TRD diagnosis: Patient must have failed at least two adequate trials of different antidepressants
2. Screen for contraindications:
   • Aneurysmal vascular disease
   • History of intracerebral hemorrhage
   • Uncontrolled hypertension
   • Psychotic disorders
3. Initiate treatment:
   • Start with 56mg intranasally twice weekly for 4 weeks
   • May increase to 84mg if needed and tolerated
   • Must be administered in conjunction with a newly initiated or optimized oral antidepressant
4. Monitor response:
   • Assess improvement in depressive symptoms at 24 hours and weekly
   • Continue treatment if clinically meaningful improvement occurs
5. Long-term management:
   • Gradually reduce frequency of administration based on response
   • Maintain lowest effective dose and frequency

Conclusion

Esketamine represents a significant advancement in the treatment of TRD, offering rapid symptom relief when conventional treatments have failed. Its unique mechanism of action and FDA approval make it a valuable option for this difficult-to-treat population, though careful patient selection and monitoring are essential to maximize benefits while minimizing risks.