Are there any issues with receiving Spravato (esketamine) concurrently with electroconvulsive therapy (ECT) that uses ketamine as the anesthetic agent?

Concurrent Spravato and ECT with Ketamine Anesthesia: Safety Considerations

There are significant theoretical and documented safety concerns with receiving Spravato (esketamine) concurrently with ECT using ketamine as the anesthetic agent, primarily related to cumulative NMDA receptor antagonism, serotonin syndrome risk, and cardiovascular effects—this combination should be approached with extreme caution and close monitoring, if used at all.

Key Safety Issues

1. Cumulative NMDA Receptor Effects

Both esketamine (Spravato) and ketamine are NMDA receptor antagonists acting through the same mechanism. Using ketamine as the ECT anesthetic while a patient is receiving regular Spravato treatments creates:

• Additive dissociative effects: The Spravato FDA label warns about dissociation, sedation, and cognitive impairment 1. Combining with ketamine anesthesia compounds these risks
• Tolerance development: The FDA label explicitly notes that "tolerance would be expected with prolonged use of esketamine" 1, and concurrent ketamine exposure may accelerate this process, potentially reducing therapeutic efficacy of both agents
• Abuse liability concerns: Both are Schedule III controlled substances with documented abuse potential 1

2. Serotonin Syndrome Risk

A critical case report documented recurrent serotonin syndrome in a patient receiving ketamine-assisted ECT 2. The mechanism involves:

• ECT transiently increases blood-brain barrier permeability, elevating brain antidepressant levels
• Ketamine increases serotonin release through glutamate-AMPA receptor pathways
• Combined ECT and ketamine can dangerously amplify serotonergic transmission
• This risk is magnified when patients are on concurrent SSRIs/SNRIs, which is required for Spravato use per FDA approval 1

3. Cardiovascular Concerns

Both agents cause blood pressure elevation:

• Spravato requires pre- and post-administration blood pressure monitoring 1
• ECT itself causes transient cardiovascular stress
• Ketamine anesthesia adds additional hemodynamic burden
• Cumulative hypertensive effects could be particularly dangerous in patients with cardiovascular risk factors

4. Cognitive and Dissociative Effects

• Spravato causes cognitive impairment requiring patients not to drive until the next day after restful sleep 1
• ECT causes post-ictal confusion and memory impairment 3
• Ketamine anesthesia adds its own dissociative and cognitive effects
• Triple burden on cognition may be clinically significant and prolonged

Evidence on Combined Use

Limited Supporting Data

One small case series (n=4) described combining ECT with intranasal esketamine on non-ECT days over 24 weeks, showing feasibility with mild adverse events 4. However:

• This was naturalistic, uncontrolled data
• Esketamine was given on separate days from ECT, not concurrently
• No patients received ketamine as the ECT anesthetic

Esketamine as ECT Anesthetic (Different Question)

Recent trials examined esketamine replacing standard anesthetics for ECT:

• Non-inferior to propofol for depression outcomes 5
• May improve suicidal ideation remission 6
• But these studies did NOT involve concurrent Spravato treatment—they used esketamine only as the anesthetic agent

Clinical Recommendations

If This Combination Is Being Considered:

Strongly prefer alternative approaches:

1. Use standard ECT anesthetics (methohexital, propofol, etomidate) instead of ketamine 3
2. Temporal separation: If both treatments are deemed necessary, space Spravato and ECT sessions by at least 48-72 hours to minimize overlap
3. Sequential rather than concurrent: Complete one treatment course before initiating the other

If Concurrent Use Proceeds Despite Risks:

Mandatory monitoring includes:

• Cardiovascular: Blood pressure monitoring before, during, and for extended periods after both treatments
• Serotonin syndrome surveillance: Monitor for mental status changes, autonomic instability, neuromuscular abnormalities (especially if on SSRIs/SNRIs, which is required for Spravato) 2
• Cognitive assessment: Extended post-treatment observation periods beyond standard protocols
• Dissociative symptoms: Enhanced monitoring for at least 2 hours post-Spravato (per FDA requirements) 1 and extended post-ECT observation

Contraindications are absolute:

• Spravato is contraindicated in patients with aneurysmal vascular disease, arteriovenous malformations, or intracerebral hemorrhage 1—ECT in these patients would compound risk

Critical Pitfalls to Avoid

1. Do not assume safety based on esketamine-as-anesthetic studies—these did not involve concurrent Spravato treatment
2. Do not overlook serotonin syndrome risk—the case report demonstrates this is a real, recurrent danger 2
3. Do not use standard monitoring protocols—this combination requires enhanced, prolonged observation
4. Do not ignore the 2004 ECT guideline recommendation to "discontinue all medications, particularly psychotropics, while a patient is receiving ECT" whenever possible 3

Bottom Line

The 2022 VA/DoD guideline supports both ketamine/esketamine and ECT for treatment-resistant depression 7, but provides no guidance on concurrent use. The older ECT guidelines recommend avoiding concurrent psychotropics when possible 3. Given documented serotonin syndrome risk, cumulative NMDA effects, and cardiovascular concerns, this specific combination—Spravato treatment with ketamine-anesthetized ECT—represents an evidence-poor, high-risk scenario that should be avoided unless no alternatives exist, and then only with intensive monitoring protocols.