Can Spravato (esketamine) precipitate mania?

Can Spravato Precipitate Mania?

Yes, Spravato (esketamine) can precipitate mania or hypomania in patients with bipolar disorder, though the risk appears lower during acute treatment phases and increases during maintenance therapy.

Evidence for Mania Risk with Esketamine

The most relevant and recent evidence comes from a real-world study of ketamine/esketamine in bipolar depression, which found that no patients experienced mania or hypomania during the acute treatment phase (twice-weekly dosing for up to 4 weeks), but 28.9% (13/45 patients) developed hypomanic or manic symptoms during the maintenance phase, representing approximately 1 event per 2.7 patient-years 1. Importantly, only 1 of these 16 manic/hypomanic events was severe enough to require hospitalization 1.

Risk Stratification by Treatment Phase

Acute Phase (Lower Risk)

• During intensive twice-weekly treatment for up to 4 weeks, the risk of affective switch appears minimal 1
• This suggests that closely monitored, frequent dosing may be safer than intermittent maintenance dosing 1

Maintenance Phase (Higher Risk)

• The risk of mania/hypomania substantially increases during ongoing maintenance treatment, with nearly 30% of patients experiencing mood elevation 1
• This pattern differs from traditional antidepressants where mood switching often occurs early in treatment 2

Comparison to Traditional Antidepressants

Traditional antidepressants carry well-established mania risk in bipolar patients:

• Antidepressants can induce mania in patients with pre-existing bipolar disorder, particularly tricyclics and MAOIs 3
• SSRIs like escitalopram can cause dose-dependent treatment-emergent mania, with symptoms emerging within 1 month of dose escalation 2
• A retrospective review found 58% of youths with bipolar disorder experienced manic symptoms after exposure to mood-elevating agents, most commonly antidepressants 4

FDA Labeling and Contraindications

The FDA label for Spravato does not list bipolar disorder as a contraindication, but importantly:

• Spravato has not been studied in patients with bipolar disorder and is not indicated for this population 5
• The FDA label warns about increased risk of suicidal thoughts and actions in patients under 24 years, particularly within the first few months of treatment 6
• Patients with a history of psychosis should be carefully evaluated, as Spravato can cause dissociation and perceptual disturbances 6

Clinical Management Algorithm

Before Initiating Esketamine:

• Ensure adequate mood stabilization with lithium, valproate, or atypical antipsychotics before considering esketamine 7
• Screen for personal and family history of bipolar disorder, as undiagnosed bipolar patients are at highest risk 8
• Obtain baseline mood assessment using standardized scales 1

During Acute Treatment:

• Monitor closely for early signs of activation, including decreased need for sleep, increased energy, racing thoughts, or impulsivity 7
• The 2-hour post-administration monitoring period required by the REMS program provides opportunity to assess for acute mood changes 6
• Continue concurrent mood stabilizer therapy throughout treatment 5

During Maintenance Phase:

• Increase vigilance for hypomanic/manic symptoms as risk appears higher during this phase 1
• Consider more frequent mood monitoring (weekly to biweekly) rather than monthly 1
• Maintain therapeutic levels of mood stabilizers, as withdrawal increases relapse risk by over 90% 9

Important Caveats

Distinguishing activation from true mania is critical: Behavioral activation or agitation may occur early in treatment with any antidepressant and does not necessarily indicate bipolar disorder 4. True manic episodes involve sustained mood elevation, decreased need for sleep, and functional impairment 7.

The mechanism of esketamine-induced mania may differ from traditional antidepressants: The delayed emergence during maintenance rather than acute treatment suggests a different pathophysiology than SSRI-induced mood switching 1.

Single case reports exist demonstrating safety: One case report showed successful use of intranasal esketamine in a bipolar patient on mood stabilizers without inducing mania 5, but this represents insufficient evidence to establish safety.

Risk Mitigation Strategy

If esketamine is used in bipolar depression (off-label):

• Never use as monotherapy; always combine with adequate mood stabilization 7, 5
• Limit to acute treatment series when possible, as maintenance appears riskier 1
• Implement structured mood monitoring with validated scales at each visit 1
• Educate patients and families about early warning signs of mood elevation 9
• Have a predetermined plan for managing emergent hypomania (dose reduction, increased mood stabilizer, or discontinuation) 7

The safest approach remains using FDA-approved treatments for bipolar depression (lithium, lamotrigine, quetiapine, or olanzapine-fluoxetine combination) before considering esketamine 9.