What are the recently FDA-approved antidepressant medications that show great promise for treatment-resistant depression?

Recently FDA-Approved Antidepressants Showing Great Promise

Esketamine (Spravato) nasal spray is the most significant recent FDA-approved antidepressant, specifically indicated for treatment-resistant depression in adults, either as monotherapy or combined with an oral antidepressant, and represents a breakthrough with its novel NMDA receptor antagonist mechanism and rapid onset of action. 1

FDA-Approved Indication and Clinical Context

• Esketamine received FDA approval for treatment-resistant depression (TRD), defined as failure to respond to at least two adequate antidepressant trials with different mechanisms of action 1, 2
• The medication is also approved for depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior, when used in conjunction with an oral antidepressant 1
• This represents the first non-monoaminergic-based antidepressant approved for TRD in decades, addressing a critical unmet need 3

Evidence of Efficacy

Treatment-Resistant Depression

• Esketamine combined with a newly initiated oral antidepressant demonstrated statistically significant superiority over antidepressant plus placebo at day 28, with a difference in Montgomery-Åsberg Depression Rating Scale (MADRS) score of -4.0 points (95% CI: -7.31 to -0.64) 4
• Clinically meaningful improvement was observed at earlier time points, supporting the rapid-acting nature of this medication 4
• Meta-analysis data shows intranasal esketamine has significant efficacy in reducing depression symptoms (Hedges' g = 0.31, p < 0.001) compared to placebo 5

Optimal Dosing

• Esketamine doses of 56-84 mg demonstrate superior efficacy compared to 28 mg, with the best response found between 56 and 84 mg for reducing depressive symptoms 5
• The FDA-approved dosing involves 56 or 84 mg administered twice weekly during the induction phase 1
• Evidence suggests that higher doses within this range do not necessarily provide additional benefit, making 56-84 mg the optimal therapeutic window 5

Rapid Onset of Action

• Esketamine demonstrates rapid antidepressant effects, distinguishing it from traditional antidepressants that require 4-6 weeks for full effect 6
• This rapid onset is particularly valuable for patients with acute suicidal ideation, though the FDA label clarifies that effectiveness in preventing suicide has not been demonstrated 1
• The medication addresses the critical gap where traditional antidepressants fail to provide robust and rapid relief of suicidal ideation 6

Safety Profile and Monitoring Requirements

Common Adverse Events

• The five most common adverse events are dissociation, nausea, vertigo, dysgeusia, and dizziness, all occurring more frequently with esketamine than placebo 4
• These adverse events generally appear shortly after dosing and resolve within 1.5 hours 4
• Discontinuation due to adverse events occurred in 7% of patients receiving esketamine plus antidepressant versus 0.9% with placebo 4

Critical Safety Warnings (FDA Boxed Warnings)

• Risk for sedation, dissociation, and respiratory depression requires monitoring patients for at least two hours after administration 1
• Potential for abuse and misuse necessitates careful patient selection and monitoring for signs of abuse 1
• Increased risk of suicidal thoughts and behaviors in young adults requires close monitoring, though esketamine is not approved for pediatric use 1

Contraindications

• Absolute contraindications include aneurysmal vascular disease, arteriovenous malformation, intracerebral hemorrhage, and hypersensitivity to esketamine or ketamine 1
• Blood pressure must be assessed before and after administration due to risk of increases 1
• Patients cannot drive or operate machinery until the next day after a restful sleep 1

REMS Program Requirement

• Esketamine is only available through a restricted program called the SPRAVATO REMS, reflecting its controlled substance status (Schedule III) and safety concerns 1
• Administration must occur under healthcare provider supervision in a certified healthcare setting 1
• This requirement ensures appropriate monitoring but may limit accessibility compared to traditional oral antidepressants 7

Treatment Algorithm Position

When to Consider Esketamine

• Esketamine should be considered for highly refractory cases after failure of multiple augmentation strategies 2, 8
• The evidence base for atypical antipsychotic augmentation (aripiprazole, quetiapine, olanzapine) remains more extensive and should typically be tried first 9
• Esketamine represents a second-line or third-line option after conventional augmentation strategies have failed 2, 9

Duration of Treatment

• Evidence of therapeutic benefit should be evaluated at the end of the 4-week induction phase to determine need for continued treatment 1
• For patients with acute suicidal ideation, treatment beyond 4 weeks has not been systematically evaluated 1
• Long-term efficacy and safety data remain limited, representing a gap in current evidence 3

Clinical Advantages Over Traditional Approaches

• Esketamine offers a novel mechanism of action (NMDA receptor antagonism) distinct from monoaminergic antidepressants, providing an option for patients who have failed multiple traditional treatments 3, 7
• The rapid onset addresses the critical period when patients are most vulnerable, particularly those with suicidal ideation 6
• It provides an alternative to electroconvulsive therapy (ECT), which may not reduce suicidal ideation for 1-2 weeks 6

Important Caveats and Limitations

Evidence Quality Concerns

• Some trials did not report significant effects on depressive symptom severity with esketamine in TRD, indicating caution is warranted 3
• One Phase 3 trial (TRANSFORM-1) did not achieve statistical significance for its primary endpoint with the 84 mg dose, though the 56 mg dose showed nominal significance 10
• Overall quality of evidence from meta-analyses is low, limited by small numbers of studies and high publication bias 5

Unanswered Questions

• Insufficient data exists to formulate specific guidelines about optimal duration of esketamine administration 3
• Evidence about favorable or negative prognostic factors for this treatment is lacking 3
• The comparative efficacy of esketamine versus off-label racemic ketamine remains unclear 7
• Long-term addictive potential requires further study 7

Cost and Access Barriers

• The REMS program requirements, need for supervised administration, and monitoring may limit practical use despite FDA approval 7
• Cost considerations may position esketamine less favorably compared to generic alternatives, despite its novel mechanism 7

Comparison to Other Recent Developments

• No other antidepressants have received FDA approval for treatment-resistant depression in recent years with comparable evidence 3
• Brexanolone was approved for postpartum depression but not for TRD 3
• Traditional augmentation strategies (aripiprazole, lithium, thyroid hormone) remain the primary first-line approaches with more extensive evidence bases 2, 9