Esketamine Nasal Spray: Managing Dissociation, Blood Pressure Spikes & Monitoring Guidelines

When a patient with treatment‑resistant depression (TRD) finally finds a medication that lifts their mood in hours rather than weeks, the excitement can be huge. Esketamine nasal spray delivers that rapid relief, but it also brings unique safety challenges-most notably dissociation and sharp, short‑lived blood‑pressure spikes. Understanding why these effects happen, how severe they can be, and what the FDA‑mandated monitoring looks like can turn anxiety into confidence for clinicians and patients alike.

What is Esketamine Nasal Spray?

Esketamine nasal spray is a prescription medication sold under the brand name Spravato. It is approved by the U.S. Food and Drug Administration (FDA) for adults with major depressive disorder who have not responded to at least two other antidepressants. Developed by Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, the drug is delivered as a 28 mg, 56 mg, or 84 mg spray that patients self‑administer in a certified clinic.

How Esketamine Works: The NMDA Connection

The molecule is the S‑enantiomer of ketamine and acts as a non‑competitive antagonist at the NMDA receptor. By blocking the receptor’s PCP binding site, it reduces calcium influx caused by glutamate. This inhibition is strongest on NMDA receptors located on GABA‑ergic interneurons, which leads to a burst of excitatory firing across cortical networks. The result is a rapid surge in synaptic plasticity that translates into fast‑acting antidepressant effects-a mechanism very different from traditional monoamine‑based drugs.

Dissociation: Frequency, Symptoms, and Management

Across the three pivotal phase‑3 trials (TRANSFORM‑1, ‑2, and ‑3), the FDA reported that 56.2% of patients experienced some level of dissociation versus 13.9% on placebo. The peak typically occurs around 40 minutes after dosing and resolves within 1.5-2 hours. Severe dissociation (CADSS score ≥3) was seen in about 6% of participants.

Common sensations include:

• Feeling detached from one’s body or environment
• Altered sense of time (minutes feel like seconds)
• Visual distortions or dream‑like imagery

Because the effect is dose‑dependent, the 84 mg spray produces dissociation in roughly 61% of users, compared with 54% at 56 mg. Management relies on a calm setting, minimal external stimuli, and reassurance that the experience is temporary. In rare cases of severe distress, clinicians may administer a short‑acting benzodiazepine, though this occurs in less than 2% of treatments.

Blood Pressure Spikes: What the Numbers Show

Transient hypertension is another predictable reaction. In pooled trial data, 32.7% of patients had a systolic rise of 14-23 mmHg and a diastolic rise of 7-16 mmHg, usually peaking at the same 40‑minute mark as dissociation. Most elevations are asymptomatic and revert to baseline within two hours. However, individuals with uncontrolled hypertension (systolic >160 mmHg or diastolic >100 mmHg) are excluded from treatment because the spikes can pose cardiovascular risk.

Key monitoring figures:

• Baseline BP measured 5 minutes before administration
• Repeat measurements every 5-10 minutes until the 40‑minute peak
• Final check before discharge at 2 hours post‑dose

Monitoring Protocols Under the REMS Program

The FDA’s Risk Evaluation and Mitigation Strategy (REMS) is the most rigorous safety framework for any antidepressant. Its core requirements include:

1. Administration only in a certified health‑care setting.
2. Pre‑treatment assessment of vital signs, mental status, and consent to the Patient‑Provider Agreement.
3. Direct observation for a minimum of 2 hours after each spray.
4. Standardized dissociation assessment using the Clinician‑Administered Dissociative States Scale (CADSS) at the 40‑minute mark.
5. Immediate availability of emergency equipment (oxygen, IV lines, benzo rescue).

Most clinics follow a structured timetable, as shown in the table below.

Practical Tips for Clinicians and Patients

Both sides benefit from clear communication:

• Pre‑treatment education: Explain that dissociation feels like a short dream and that BP spikes are temporary. Patients who know what to expect report lower anxiety.
• Environment control: Dim lighting, soft music, and a quiet room reduce overstimulation during the dissociative window.
• Vital‑sign automation: Electronic monitors that flag BP > 150/95 mmHg cut down on manual errors and speed up discharge decisions.
• Follow‑up scheduling: Arrange the next dose after confirming the previous session’s CADSS score was < 10 and BP returned to baseline.

Patients with a history of hypertension should coordinate with their primary care physician to optimize antihypertensive therapy before starting Spravato. If a patient experiences a systolic reading > 170 mmHg despite medication, the clinician should pause treatment and reassess cardiovascular risk.

Future Directions: Personalizing Monitoring

Recent data from the SUSTAIN‑2 trial suggest that a subset of patients-those with stable vitals and low CADSS scores after the first hour-may safely reduce monitoring to 1 hour. The FDA has already approved a protocol amendment to allow such tailored schedules, pending clinic‑level validation.

Digital health startups are also entering the space. Wearable devices that stream real‑time BP and heart‑rate data to the clinic’s EMR can trigger an automatic alert if thresholds are crossed. In parallel, a mobile app that administers a brief self‑report of dissociation (using the Patient Dissociative State Scale) could supplement in‑person CADSS scoring, especially in tele‑health‑enabled Spravato programs.

Despite tech advances, experts agree that the acute physiological effects stem from the drug’s NMDA antagonism, making some level of observation unavoidable. The challenge now is to make that observation less burdensome while keeping safety front‑and‑center.

Key Takeaways

• Esketamine nasal spray provides rapid relief for TRD but reliably produces transient dissociation and BP spikes.
• Incidence peaks at ~40 minutes; most symptoms resolve by 2 hours.
• The FDA‑mandated REMS protocol requires a minimum 2‑hour monitored stay, CADSS assessment, and frequent BP checks.
• Patient education, calm environments, and automated monitoring improve safety and satisfaction.
• Emerging evidence supports shorter monitoring for low‑risk patients and digital tools that could streamline future care.