Can a patient with bipolar disorder take Spravato (esketamine)?

Can a Bipolar Patient Take Spravato?

Yes, patients with bipolar disorder can take Spravato (esketamine), but only when combined with a mood stabilizer and after careful consideration of the risk-benefit profile, particularly the risk of affective switch during maintenance treatment.

Current Evidence and FDA Status

The FDA has not approved esketamine specifically for bipolar depression, and the manufacturer explicitly states that esketamine "has not been studied, and is not indicated, for patients with bipolar disorder" 1. However, emerging real-world evidence suggests it can be used safely and effectively in this population with appropriate precautions.

Efficacy in Bipolar Depression

• Real-world effectiveness data demonstrates that esketamine produces significant improvement in bipolar depression, with 39% of patients achieving clinical response (≥50% improvement on MADRS) and 13.2% achieving remission following an acute treatment series 2.

• A multicentric naturalistic study found no significant differences in response or remission rates between bipolar treatment-resistant depression (B-TRD) and unipolar TRD patients treated with esketamine, with both groups showing significant reduction in depressive symptoms at one and three months follow-up 3.

• Esketamine demonstrated greater anxiolytic effects in bipolar patients compared to unipolar depression patients, which may provide additional therapeutic benefit 3.

Critical Safety Considerations: Risk of Affective Switch

The most important clinical concern is the risk of treatment-emergent mania or hypomania, which follows a distinct temporal pattern:

• During the acute treatment phase (twice-weekly dosing for up to 4 weeks), NO patients experienced mania or hypomania in the largest real-world cohort study 2.

• However, during the maintenance phase, 28.9% of patients experienced hypomanic or manic symptoms at some point, translating to approximately 1 event per 2.7 patient-years of treatment 2.

• Most affective switches were mild to moderate in severity, with only 1 out of 16 manic/hypomanic events being severe enough to require hospitalization 2.

• Another study found improvement in depressive symptoms was NOT associated with treatment-emergent affective switch, supporting the safety profile when used appropriately 3.

Mandatory Requirements for Use in Bipolar Disorder

1. Concurrent Mood Stabilizer Therapy

Esketamine must NEVER be used as monotherapy in bipolar disorder 4, 5. The patient must be on an established mood stabilizer regimen, which includes:

• Lithium (preferred for its anti-suicide properties, reducing suicide attempts 8.6-fold) 5
• Valproate 4
• Lamotrigine (particularly effective for preventing depressive episodes) 5
• Atypical antipsychotics (aripiprazole, olanzapine, quetiapine) 4

2. Patient Selection Criteria

Esketamine should be reserved for bipolar patients who:

• Have treatment-resistant bipolar depression (failed at least 2 adequate trials of antidepressants with mood stabilizers) 6
• Are currently stable on mood stabilizer therapy without recent manic or hypomanic episodes 1
• Have no history of rapid cycling (as antidepressants can induce rapid cycling) 1
• Require rapid symptom relief, particularly with suicidal ideation 6, 7

3. Administration and Monitoring Protocol

Follow the REMS (Risk Evaluation and Mitigation Strategy) requirements 6:

• Treatment must occur in certified healthcare settings
• Mandatory 2-hour post-treatment monitoring for dissociation, sedation, and blood pressure changes
• Pharmacy and healthcare setting certification required

Specific monitoring for bipolar patients includes:

• Baseline assessment: Document current mood state, recent history of mania/hypomania, current mood stabilizer regimen and levels 4
• During acute phase (weeks 1-4): Monitor for early signs of hypomania/mania at each visit (increased energy, decreased need for sleep, racing thoughts, impulsivity) 2
• During maintenance phase: Increase vigilance for affective switch, with monthly mood assessments recommended given the 28.9% risk during this period 2
• Ongoing mood stabilizer monitoring: Continue regular therapeutic drug monitoring for lithium or valproate levels 4

Treatment Algorithm for Bipolar Depression

When considering esketamine for a bipolar patient, follow this decision pathway:

1. Confirm diagnosis and current mood state: Patient must have bipolar depression (not mixed episode or mania) confirmed by DSM criteria 2

2. Verify treatment resistance: Document failure of at least 2 adequate antidepressant trials (with mood stabilizers) at therapeutic doses for sufficient duration 6

3. Ensure mood stabilizer optimization: Patient must be on therapeutic doses of lithium, valproate, or other mood stabilizers with documented therapeutic levels where applicable 1, 3

4. Assess recent mood stability: No manic or hypomanic episodes in recent months (specific timeframe not defined in evidence, but clinical judgment suggests at least 3-6 months of stability) 1

5. Evaluate suicide risk: Esketamine is particularly appropriate for patients with acute suicidal ideation requiring rapid intervention 6, 7

6. Initiate acute treatment: Begin twice-weekly esketamine with close monitoring for 4 weeks 2

7. Reassess after acute phase: If response achieved, transition to maintenance dosing with heightened vigilance for affective switch 2

Common Pitfalls to Avoid

• Never use esketamine as monotherapy in bipolar disorder - this violates fundamental principles of bipolar treatment and dramatically increases risk of affective switch 4, 5

• Do not assume the acute phase safety profile extends to maintenance treatment - the risk of mania/hypomania emerges primarily during maintenance, not acute treatment 2

• Avoid using esketamine in patients with recent or frequent manic episodes - these patients are at higher baseline risk for affective switch 1

• Do not discontinue or reduce mood stabilizers when starting esketamine - maintain therapeutic levels throughout treatment 1, 3

• Failing to educate patients and families about early warning signs of hypomania/mania - given the 28.9% risk during maintenance, early detection is critical 2

Comparison to Traditional Antidepressants

Esketamine may offer advantages over traditional antidepressants in bipolar depression:

• Traditional antidepressants are "commonly associated with having the potential to induce rapid cycling" with poorly understood mechanisms 1
• The low rate of severe affective switches with esketamine (only 1 hospitalization out of 16 events) suggests it may be better tolerated than some traditional antidepressants 2
• However, the 28.9% overall risk of hypomania/mania during maintenance still requires careful consideration 2

Evidence Quality and Limitations

The current evidence base has significant limitations:

• All studies excluded bipolar patients from FDA approval trials 1
• Real-world evidence comes from small samples (largest study n=45 bipolar patients) 2
• No head-to-head comparisons exist between esketamine and other treatment options for bipolar depression 3, 8
• Long-term safety data beyond a few years is lacking 6
• The quality of systematic reviews and original studies is generally poor, resulting in low certainty of evidence 8

Despite these limitations, the consistent findings across multiple real-world studies support cautious use in appropriately selected patients 2, 3.