Ketamine Approval Status for Depression
Yes, esketamine (the S-enantiomer of ketamine) has been FDA-approved since 2019 for treatment-resistant depression in adults, while racemic ketamine itself remains off-label for depression despite widespread clinical use. 1
FDA-Approved Formulation
Esketamine (Spravato®) is FDA-approved as an intranasal spray for two specific indications:
- Treatment-resistant depression (TRD) in adults, either as monotherapy or combined with an oral antidepressant 1
- Depressive symptoms in adults with major depressive disorder (MDD) who have acute suicidal ideation or behavior, used alongside an oral antidepressant 1
Critical limitation: The FDA explicitly states that esketamine's effectiveness in preventing suicide or reducing suicidal ideation/behavior has not been established 2, 1
REMS Requirements for Esketamine
Esketamine is only available through a restricted Risk Evaluation and Mitigation Strategy (REMS) program that mandates: 2, 1
- Pharmacy and healthcare setting certification
- Administration under direct medical supervision
- Mandatory 2-hour post-treatment monitoring for sedation, dissociation, and respiratory depression
- Blood pressure assessment before and after administration
Racemic Ketamine Status
Intravenous racemic ketamine remains off-label for depression but is widely used in clinical practice based on substantial evidence. 2 The 2022 VA/DoD Clinical Practice Guidelines represent a major shift from their 2016 position, now suggesting ketamine or esketamine as treatment options for patients who have failed at least 2 adequate antidepressant trials. 2
Clinical Positioning
Both ketamine and esketamine are explicitly NOT recommended as initial treatment but are reserved exclusively for patients who: 2
- Have failed at least 2 adequate pharmacologic trials at appropriate doses and durations
- Have not tolerated previous antidepressant therapies
- Meet criteria for treatment-resistant depression
Evidence Base and Efficacy Timeline
Rapid onset but limited duration characterizes both formulations:
- Significant improvement in depressive symptoms occurs within 24 hours after single-dose ketamine administration 2
- Effects persist for 3-7 days when ketamine is added to ongoing antidepressant treatment 2, 3
- Ketamine monotherapy shows no significant differences from controls at 7 days 2
- Esketamine as augmentation therapy (twice-weekly dosing) improves symptoms and remission rates up to 28 days 2
Major Safety Gaps
The most significant limitation is the absence of long-term safety and efficacy data for both formulations in MDD. 2, 4 Short-term adverse effects include: 1, 5
- Dissociative symptoms (transient, occurring around time of treatment)
- Hypertension requiring blood pressure monitoring
- Sedation and potential respiratory depression
- Confusion/agitation
Concerns requiring ongoing surveillance include: 6, 5
- Potential for abuse and misuse (both are Schedule III controlled substances)
- Unknown neurocognitive effects with long-term use
- Possible urologic toxicity with chronic administration
- Risk of substance use disorder development
Comparative Effectiveness
Real-world observational data suggests IV ketamine may achieve remission faster than intranasal esketamine (requiring fewer treatments to reach remission), though both show similar overall response and remission rates. 7 However, this finding requires confirmation in randomized controlled trials.
Common Pitfalls to Avoid
- Do not use as first-line treatment – both formulations are reserved for treatment-resistant cases only 2
- Do not assume suicide prevention efficacy – despite approval for acute suicidal ideation, effectiveness in preventing suicide is unestablished 2, 1
- Do not skip the 2-hour monitoring period for esketamine – this is a mandatory REMS requirement 2, 1
- Do not continue indefinitely without reassessment – evaluate therapeutic benefit at 4 weeks to determine need for continued treatment 1