Esketamine (Spravato) Patient Guide: Benefits, Dosing, and Side Effects Explained

This guide is adapted from the clinician guide authored by Sebastián Malleza, M.D., M.Sc. at the Psychopharmacology Institute. For the complete clinical resource, visit: Esketamine Guide: Pharmacology, Indications, Dosing Guidelines and Adverse Effects

What is Esketamine?

Esketamine (brand name Spravato) is a nasal spray medication approved for treatment-resistant depression and major depression with suicidal thoughts[1]. Unlike traditional antidepressants that can take weeks to work, esketamine can provide relief within 24 hours[17,18]. It works differently from other antidepressants by blocking NMDA receptors in the brain, which affects glutamate signaling[1,2].

Your doctor might consider adding esketamine when:

• You need rapid improvement (works within 24 hours vs. weeks for traditional antidepressants)
• You’ve tried at least 2 different antidepressants without success
• You need a “response accelerator” while waiting for oral antidepressants to work[19]
• Standard antidepressants haven’t been effective or tolerated

Esketamine may NOT be appropriate if you:

• Cannot attend required in-office treatment sessions with monitoring
• Have cardiovascular problems (especially uncontrolled high blood pressure)
• Have a history of psychosis or substance use disorders
• Have breathing problems
• Are concerned about cost or access (requires specialized facility)
• Need long-term maintenance as the primary goal (limited long-term data)

How Does This Medication Work?

Esketamine works through a unique mechanism compared to traditional antidepressants[1,2,5]:

1. Blocks NMDA receptors: It’s an NMDA receptor antagonist, blocking glutamate activity
2. Increases brain plasticity: Promotes the release of BDNF (brain-derived neurotrophic factor) and activates pathways that help form new connections in the brain[5,8,9]
3. Rapid action: These effects happen much faster than conventional antidepressants, which is why improvement can occur within 24 hours[9]

How to Take This Medication

Esketamine is very different from other antidepressants – it requires special administration:

Key Requirements

• Must be given in a certified healthcare facility (REMS program)
• Healthcare provider must supervise each dose
• You cannot take this medication home
• Someone must drive you home after each treatment

Before Each Treatment

• Don’t eat for at least 2 hours before
• Don’t drink liquids for at least 30 minutes before
• If you use nasal sprays/decongestants, use them at least 1 hour before
• Arrange transportation – you CANNOT drive on treatment day[1]

During Treatment

• The device delivers 2 sprays (14 mg each) = 28 mg total per device
• For 56 mg dose: Use 2 devices with 5-minute rest between
• For 84 mg dose: Use 3 devices with 5-minute rest between
• Don’t prime the device before use[1]

After Treatment Monitoring

You must stay at the facility for at least 2 hours while staff monitor:

• Blood pressure (checked before dosing and ~40 minutes after)
• Breathing and oxygen levels
• Overall stability before discharge[1]

Typical Dosing

For Treatment-Resistant Depression

First 4 weeks (Induction):

• 56 mg twice weekly
• May increase to 84 mg twice weekly based on response

Weeks 5-8 (Maintenance):

• 56 mg or 84 mg once weekly

Week 9 and beyond:

• 56 mg or 84 mg once weekly OR every 2 weeks
• Use lowest frequency that maintains improvement[1]

For Depression with Suicidal Thoughts

• 84 mg twice weekly for 4 weeks
• May reduce to 56 mg if side effects occur
• Use beyond 4 weeks hasn’t been studied for this indication[1]

Common Side Effects

Most side effects occur during or shortly after treatment and typically resolve within 2 hours.

Most Common Side Effects

Dissociation (28-48%)[1,15]

• Feeling disconnected from yourself or surroundings
• May involve changes in perception, feeling “spaced out”
• Usually starts shortly after dosing and resolves within 2 hours
• Often becomes less intense with repeated treatments
• Main reason people stop treatment for depression with suicidal thoughts

Dizziness (22-45%)[1,26]

• More common with depression with suicidal thoughts
• Usually temporary

Sedation/Sleepiness (6-29%)[1]

• May feel very drowsy or even lose consciousness (rare: 0.3-0.4%)
• This is why you must be monitored for 2 hours
• Don’t drive or operate machinery until the next day after restful sleep

Nausea (25-32%)[1]

• Most common stomach side effect
• Usually lasts less than 1 hour
• Fasting before treatment helps reduce this

Other Common Side Effects:

• Headache (19%)
• Altered taste (4-20%)
• Anxiety (10-15%)
• Temporary thinking/memory problems (11-13%) – usually resolve within 2 hours[26]
• Vomiting (6-12%)
• Feeling drunk (4-7%)
• Numbness/tingling (4-13%)

Blood Pressure Increases

What to expect[1]:

• Temporary increase peaking at 40 minutes after dose
• Typical increase: 7-10 mmHg systolic, 4-6 mmHg diastolic
• 3-19% of patients have substantial increases
• Usually returns to normal within 4 hours

Why monitoring matters:

• Blood pressure checked before and after each dose
• Treatment may be delayed if your blood pressure is too high (>140/90)
• Rarely, severe increases require emergency treatment

Important Safety Information

Do NOT use esketamine if you have:

• Aneurysms (weakened blood vessels)
• Arteriovenous malformation
• History of brain bleeding
• Allergy to esketamine or ketamine[1]

Tell your doctor if you have:

• High blood pressure or heart problems
• History of stroke
• Liver problems
• History of psychosis or bipolar disorder
• History of substance abuse
• Breathing problems
• Are pregnant or breastfeeding

Drug Interactions

Tell your doctor about all medications, especially:

• Sedatives (benzodiazepines, sleep aids, opioids)
• Stimulants (can increase blood pressure effects)
• MAO inhibitors (can increase blood pressure effects)
• Nasal decongestants or corticosteroids[1]

Important: Esketamine can cause false-positive drug tests for methadone[1]

When to Contact Your Doctor Immediately

Seek immediate medical attention if you experience:

• Severe increase in blood pressure
• Difficulty breathing
• Severe sedation or loss of consciousness
• Thoughts of suicide or worsening depression
• Signs of bladder problems (painful urination, frequent urination, blood in urine)
• Severe dissociation or confusion lasting longer than expected

What to Expect with Treatment

Short-term Effects

• Rapid improvement: Many people feel better within 24 hours[17,19]
• Peak effect: Greatest improvement often seen in the first 24 hours to 1 week
• Effects may diminish over time – some experts suggest using it as a “response accelerator” early in treatment[19]

Long-term Considerations

• Effectiveness over time: Studies show mixed results
  • Effect may decrease: from 0.33 at 24 hours to 0.15 at 2 weeks to 0.23 at 4 weeks[19]
  • Some patients maintain improvement: 49-50% remission at 2 years in long-term studies[21]
• Frequency: Most patients need weekly or every-2-week treatments long-term (75% of visits)[21]
• Commitment: Requires ongoing visits to certified facility

Special Considerations

Pregnancy and Breastfeeding

• Not recommended during pregnancy: May affect fetal brain development[1,34]
• Not recommended while breastfeeding: Passes into breast milk and may affect infant brain development[1]
• The risk to brain development may extend to age 3[1]

Older Adults

• May need lower starting dose (28 mg)
• Less effective in elderly patients with treatment-resistant depression[37]

Liver Problems

• Mild to moderate: No dose change but may need longer monitoring
• Severe: Not recommended[1]

Substance Use History

• Esketamine is a controlled substance (Schedule III) due to abuse potential
• Requires careful monitoring if you have a history of substance use
• Studies suggest minimal misuse risk in supervised medical settings[33]

Benefits of Esketamine

Patients and doctors choose esketamine because it:

• Works much faster than traditional antidepressants (24 hours vs. weeks)
• Can provide hope when other treatments have failed
• May “jump-start” recovery while waiting for other medications to work
• Offers a different mechanism when standard approaches don’t work

Potential Concerns

Serious but Rare Risks

• Bladder problems: Rare with medical use (1.1% in post-marketing reports)[28-30]
• Respiratory depression: Very rare but serious – why monitoring is required[1]
• Dependence: Physical and psychological dependence possible[1,31]
• Suicidal thoughts: Continued monitoring needed, especially early in treatment[1,19]

Practical Challenges

• Requires frequent visits to specialized facility
• Cannot drive on treatment days
• Cost and insurance coverage
• Time commitment (2+ hours per visit)
• Limited long-term effectiveness data

Important Notes

• Esketamine is ONLY available through certified REMS facilities
• You cannot fill a prescription at a regular pharmacy
• Each dose must be supervised by healthcare professionals
• Treatment requires significant time commitment
• Effects on driving last until the next day
• Regular assessment needed to determine if treatment should continue

Making the Decision

Esketamine represents a significant advancement for treatment-resistant depression, offering rapid relief when traditional medications haven’t worked. However, it requires careful consideration of:

• Your ability to attend regular supervised treatments
• Transportation arrangements
• Potential side effects during and after treatment
• Long-term commitment to ongoing sessions
• Cost and insurance coverage

Discuss these factors thoroughly with your healthcare provider to determine if esketamine is right for your situation.

References

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Disclaimer: This guide is for general informational purposes and is not a substitute for professional medical advice. Always discuss any questions about your medication with your healthcare provider.