Is Spravato (esketamine) suitable for use in bipolar disorder?

Spravato (Esketamine) in Bipolar Disorder

Spravato (esketamine) is not FDA-approved for bipolar disorder and should not be used as a standard treatment, but emerging real-world evidence suggests it may be cautiously considered for treatment-resistant bipolar depression when combined with mood stabilizers, with careful monitoring for affective switch. 1, 2, 3

Current Guideline-Based Treatment Framework

• The American Academy of Child and Adolescent Psychiatry recommends lithium, valproate, or atypical antipsychotics as first-line treatments for bipolar disorder, with no mention of esketamine in standard treatment algorithms 1, 2

• For bipolar depression specifically, the American Academy of Child and Adolescent Psychiatry recommends olanzapine-fluoxetine combination or lamotrigine as evidence-based options 1, 2

• Antidepressant monotherapy is explicitly contraindicated due to risk of mood destabilization and triggering manic episodes 1, 2

FDA Approval Status and Manufacturer Position

• Esketamine is FDA-approved only for treatment-resistant unipolar depression and major depressive disorder with suicidal ideation—patients with bipolar disorder were explicitly excluded from the pivotal clinical trials 4, 5

• The manufacturer explicitly states that esketamine "has not been studied, and is not indicated, for patients with bipolar disorder" 4

Emerging Real-World Evidence

The most recent and highest quality study (2024) from Yale Psychiatric Hospital provides the strongest evidence for esketamine use in bipolar depression: 3

• In 45 patients with treatment-resistant bipolar depression, 39% achieved clinical response (≥50% improvement on MADRS) and 13.2% achieved remission following acute treatment 3

• Critically, no patients experienced mania or hypomania during the acute treatment phase (twice-weekly dosing for up to 4 weeks) 3

• However, during maintenance treatment, 28.9% of patients experienced hypomanic or manic symptoms at some point (1 event per 2.7 patient-years), though only 1 event was severe enough to require hospitalization 3

• A 2023 multicentric naturalistic study of 35 bipolar TRD patients found significant reduction in depressive symptoms with no significant differences in response rates compared to unipolar TRD, and importantly, improvement was not associated with treatment-emergent affective switch 6

Clinical Decision Algorithm

If considering esketamine for treatment-resistant bipolar depression:

1. Ensure adequate mood stabilization first: Patient must be on therapeutic doses of lithium, valproate, or atypical antipsychotics before considering esketamine 1, 3, 6

2. Confirm treatment resistance: Patient should have failed at least two evidence-based treatments for bipolar depression (e.g., olanzapine-fluoxetine, lamotrigine, quetiapine) 1, 2

3. Risk stratification for affective switch:

   • Lowest risk: Bipolar II without recent manic episodes 4
   • Higher risk: Bipolar I with history of rapid cycling 1
   • Highest risk: Recent manic episode within 6 months 3

4. Treatment protocol:

   • Use acute phase dosing only (twice weekly for up to 4 weeks) initially, as this carries minimal switch risk 3
   • If transitioning to maintenance, increase monitoring frequency significantly, as switch risk increases to approximately 29% over extended treatment 3
   • Monitor for hypomanic/manic symptoms at every visit using standardized scales 3, 6

Critical Safety Considerations and Monitoring

• During acute phase (weeks 1-4): Monitor for dissociative symptoms, blood pressure elevation, and any early signs of mood elevation at each dosing session 3, 5

• During maintenance phase: The risk of affective switch increases substantially—implement weekly mood monitoring and have a clear plan for rapid intervention if hypomanic symptoms emerge 3

• Continue baseline mood stabilizer therapy throughout esketamine treatment without dose reduction 3, 6

• Maintain therapeutic levels of lithium or valproate with regular monitoring every 3-6 months as per standard bipolar disorder guidelines 1

Common Pitfalls to Avoid

• Never use esketamine as monotherapy in bipolar disorder—this violates the fundamental principle that antidepressants must always be combined with mood stabilizers 1, 2

• Do not assume acute phase safety translates to maintenance phase safety—the Yale study clearly demonstrates increased switch risk during maintenance treatment 3

• Avoid using esketamine in patients with inadequately controlled bipolar disorder—mood stabilization must be achieved first 1, 6

• Do not discontinue mood stabilizers prematurely—withdrawal of maintenance lithium therapy is associated with >90% relapse rates 1

Strength of Evidence Assessment

The evidence for esketamine in bipolar disorder is limited but growing. The 2024 Yale study 3 represents the largest and most recent real-world cohort, while the 2023 multicentric study 6 provides corroborating evidence from multiple centers. However, both are observational studies without randomized controls, and the total evidence base remains far weaker than for guideline-recommended treatments 1, 2.

Given the lack of FDA approval, exclusion from guidelines, and manufacturer warnings, esketamine should only be considered after exhausting all evidence-based options for treatment-resistant bipolar depression, and only with rigorous mood stabilizer coverage and intensive monitoring protocols. 1, 2, 3, 4