Is it safe to use lorazepam (Ativan) together with Spravato (esketamine) nasal spray?

Concurrent Use of Lorazepam and Spravato: Safety Considerations

Concurrent use of lorazepam with Spravato (esketamine) requires extreme caution due to the risk of respiratory depression and oversedation, and should generally be avoided unless absolutely necessary with close monitoring.

Key Safety Concerns

Respiratory Depression Risk

The combination of benzodiazepines like lorazepam with esketamine poses significant risk for respiratory depression. While esketamine clinical trials did not report respiratory depression as an adverse event 1, postmarketing surveillance has identified cases of respiratory depression associated with esketamine use, with an estimated incidence of 1 case per 20,000 treatment sessions 2.

• Benzodiazepines are central nervous system depressants that can decrease respiratory drive 3
• When benzodiazepines are combined with other CNS depressants, the risk of respiratory compromise increases substantially 4, 5
• Studies show that when benzodiazepines and opioids are used together, hypoxemia occurs in 92% of subjects and apnea in 50%, compared to no significant respiratory depression with benzodiazepines alone 4
• The ESMO guidelines specifically warn that fatalities have been reported with concurrent use of benzodiazepines with high-dose olanzapine, highlighting the serious risks of combining CNS depressants 6

Sedation and Dissociation

Esketamine already causes significant sedation (23% incidence) and dissociation (41% incidence) as monotherapy 1. Adding lorazepam would compound these effects:

• Sedation is one of the most common adverse reactions with esketamine, occurring in 23% of patients receiving esketamine plus oral antidepressant 1
• Dissociation occurs in 41% of esketamine-treated patients 1
• Lorazepam causes drowsiness, delirium, and paradoxical agitation 6
• The combination may lead to oversedation requiring lower doses of both agents if co-administration is unavoidable 6

Clinical Management Recommendations

If Concurrent Use Is Necessary

If lorazepam must be used with esketamine, implement the following precautions:

• Reduce lorazepam dose significantly - Use 0.25-0.5 mg instead of standard 0.5-1 mg doses when co-administered with other CNS depressants 6
• Monitor continuously during the 2-hour post-esketamine observation period required by the Risk Evaluation and Mitigation Strategy (REMS) program 7
• Ensure pulse oximetry monitoring is available to detect early signs of respiratory depression 2
• Have respiratory support equipment immediately available, including oxygen, suction, and bag-valve-mask ventilation 4, 8
• Ensure at least one individual capable of establishing a patent airway and providing positive pressure ventilation is present 8

Timing Considerations

Avoid administering lorazepam during the acute esketamine dosing period:

• Esketamine's cardiovascular and CNS effects peak within 40 minutes and return to baseline by approximately 1.5 hours post-dose 9
• The mandatory 2-hour observation period after esketamine administration is specifically designed to monitor for adverse effects 7
• If lorazepam is needed for anxiety management, consider administering it well before or after the esketamine treatment window 10

Alternative Approaches

Consider non-benzodiazepine alternatives for anxiety management in patients receiving esketamine:

• Evidence-based psychotherapies such as cognitive behavioral therapy (CBT) 3
• Specific antidepressants or other non-benzodiazepine medications approved for anxiety 3
• The esketamine itself may provide rapid anxiolytic effects as part of its antidepressant action 7

Common Pitfalls to Avoid

• Do not assume esketamine's safety profile in clinical trials applies to polypharmacy scenarios - The phase 3 trials excluded patients with significant comorbidities and concurrent CNS depressant use 1
• Do not rely solely on patient self-reporting of symptoms - Respiratory depression can be subclinical and require objective monitoring 4
• Do not discharge patients early from the observation period even if they appear stable, as delayed effects may occur 7
• Do not forget that elderly or frail patients require even lower doses of both medications (0.25-0.5 mg lorazepam maximum) 6